Intermediates for 18-o-alkyl-reserpic acid esters and related compounds

ABSTRACT

The invention comprises 17-lower alkoxy-18-hydroxy-3-epialloyohimbane-16-carboxylic acid esters etherified in 18-position with an alcohol of aliphatic character and with the nucleus of formula &lt;FORM:0885981/IV (b)/1&gt; in which the substituents at 16-, 17- and 18-have the same configuration as in d- or l-reserpine, their N-oxides and salts of these compounds, with the proviso that in reserpic acid esters etherified in the 18-position the ether radical bound to the 18-carbon atom and the alcohol radical of the ester contain together more than two carbon atoms, and a process for their preparation by reacting the corresponding 18-hydroxy compound or an N-oxide or salt thereof with a diazo compound of aliphatic character in the presence of a strong inorganic Lewis acid, and, if necessary, converting a resulting tertiary amine into an N-oxide, a resulting base into a salt, an N-oxide into the corresponding amine, or a salt into the corresponding base.  The preferred compounds are of the general formula &lt;FORM:0885981/IV (b)/2&gt; in which R1 is an unsubstituted or substituted lower alkyl group, R2 is lower alkyl, R3 is an unsubstituted or substituted hydrocarbon radical of aliphatic character, R4 and R5 each are hydrogen or halo atoms or lower aliphatic hydrocarbon radicals, etherified or esterified hydroxyl groups, etherified mercapto, nitro, or amino groups, halo-lower alkyl radicals, or together (in adjacent positions) from a cyclic substituent, e.g. methylene-dioxy, R6 in one of positions 5 or 6 stands for hydrogen or an alkyl radical, and salts of these compounds.  Specific examples of the R3 radical are lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, in which the lower alkyl groups may be further substituted by alkoxy, mercapto, amino, acyl groups or halogen atoms and the aryl radicals may be further substituted by lower alkyl, lower alkoxy, lower alkenyloxy, halogen, lower alkoxy carbonyloxy, halogen lower alkyl, nitro or amino groups.  Detailed examples are given and many compounds are also tabulated.  n-Propyl reserpate is prepared by treating reserpic acid with n-diazopropane.  Isopropyl, isobutyl and n-hexyl reserpates are likewise prepared from the appropriate diazo alkanes.ALSO:In preparing feeds, for poultry and other animals, containing corn meal, fat, mineral salts such as manganese sulphate, di-calcium carbonate and iodized salt, fish meal, soybean meal, corn gluten meal, corn distillers&#39; solubles and vitamins &amp;c., a portion of the corn meal previously blended with the pre-heated, liquefied fat is added to the remainder of the corn meal in a blending machine, thereafter the mineral salts, fish meal, soybean meal, corn gluten meal and corn distillers&#39; solubles are added in turn and after a uniform mixture has been obtained, vitamins A and D, calcium pantothenate, choline chloride, riboflavin, Vitamin B12 and methionine are added in that order; butylated hydroxy toluene is added and mixing is continued until a uniform product is obtained. The feed may include also dehydrated alfalfa meal.  The relative proportions of the ingredients are disclosed.ALSO:Pharmaceutical compositions having a hypotensive action comprise 17-lower alkoxy-18-hydroxy - 3 - epi - alloyohimbane - 16 - carboxylic esters etherified in 18-position with an alcohol of aliphatic character and with a nucleus of the formula &lt;FORM:0885981/VI/1&gt; (in which the substituents in 16-, 17- and 18-position have the same configuration as in d- or l-reserpine, their N-oxides and salts of these compounds, with the proviso that in the reserpic esters etherified at C18 the ether radical bound to the 18-O-atom and the alcohol radical of the ester group together contain more than two carbon atoms) together with a pharmaceutical carrier suitable for oral or parenteral use. The compositions may take the form of tablets, solutions or elixirs. Examples detail the formulation of ethyl 18-O-methyl reserpate in tablets.  Specified salts are hydrohalides, sulphates, phosphates, acetates, propionates, glycollates, lactates, pyruvates, oxalates, malonates, succinates, maleates, fumarates, malates, tartrates, citrates, ascorbates, citraconates, mono- and dihydroxymaleates, benzoates, phenylacetates, 4-aminobenzoates, 4 - hydroxybenzoates, anthranilates, cinnamates, mandelates, salicylates, 4 - aminosalicylates, 2 - phenoxybenzoates, 2 - acetoxybenzoates and methane-, ethane, 2 - hydroxyethane - and p - toluene-sulphonates.

United States Patent Office 3,119,819 Patented Jan. 28, 1964 3,119,819 INTERMEDIATES FOR IS-O-ALKYL-RESERPIC ACID ESTERS AND RELATED COMPOUNDS Michael Mullen Roblson, Berkeley Heights, and Robert Armistead Lucas, Mendham, N.J., assignors to Ciba Corporation, a corporation of Delaware No Drawing. Filed June 20, 1960, Ser. No. 37,097 18 Claims. (Cl. 260240) The present invention concerns B-epi-allo-yohimbane compounds having the nucleus of the formula:

More particularly, it relates to IS-etherified hydroxy-l7- lower alkoxy-il-epi-allo-yohimbane l6-carboxylic acid esters, salts of such compounds, N-oxides thereof and salts of such N-oxides. Apart from the already mentioned groups, the compounds may contain additional substituents; such substituents are, for example, aliphatic hydrocarbon, such as lower alkyl and the like, etherified hydroxyl, such as lower alkoxy, cycloalkyloxy, cycloalkyL lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy, lower alkylenedioxy and the like, esterified hydroxyl, such as lower alkoxy-carbonyloxy, lower alkanoyloxy, halogeno and the like, etherified mercapto, such as lower alkylmercapto and the like, nitro, amino, such as N,N-disubstituted amino and the like, halogeuo-lower alkyl or any other suitable substituent. These substituents are preferably attached to positions of the aromatic nucleus, i.e. ring A, of the molecule, which are available for substitution, i.e. positions 9, 10, 11 and/or 12; the substituents, particularly aliphatic hydrocarbon radicals, may also be attached to positions of other nuclei, particularly of the heterocyclic nucleus C.

More especially, the invention is directed to compounds of the formula:

in which R represents lower alkyl or substituted lower alkyl, such as, for example, etherified hydroxy-lower alkyl, e.g. lower alkoxy-lower alkyl and the like, as well as tertiary amino-lower alkyl, e.g. N,N-di-lower alkylamino-lower alkyl and the like, R, stands for lower alkyl, R, represents aliphatic hydrocarbon, particularly lower alkyl and the like, or substituted aliphatic hydrocarbon, such as, for example, etherified hydroxy-lower alkyl, e.g. lower alkoxy-lower alkyl and the like, tertiary aminolower alkyl, e.g. N,N-di-lower alkyl-amino and the like,

each of the radicals R, and R stands for hydrogen, lower aliphatic hydrocarbon, especially lower alkyl, etherified hydroxyl, particularly lower alkoxy, halogeno, or etherified mercapto, particularly lower alkyl-mercapto, as well as other etherified hydroxyl groups, such as cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy and the like, esterifiecl hydroxyl, e.g. lower alkoxy-carbonyloxy, lower alkanoyloxy and the like, nitro, amino, e.g. N,N-di-substituted amino and the like, or halogeno-lower alkyl, or, when attached to adjacent positions and taken together, for lower alkylenedioxy, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl, salts thereof, N-oxides thereof or salts of such N-oxides, as well as process for the preparation of such compounds.

The radical of the alcohol portion of the ester grouping attached to the 16-position of the molecule, which is also represented by the group R in the above formula, stands primarily for a lower alkyl group containing from one to seven, preferably from one to four, carbon atoms; such groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, as well as n-pentyl, isopentyl, n-hexyl, n-heptyl, and the like.

The esterifying group of the ester grouping attached to the l6-position of the molecule, represented, for example, by the radical R in the formula, may also stand for a substituted lower alkyl radical, such as, for example, etherified hydroxy-lower alkyl, as well as tertiary amino-lower alkyl and the like. An etherified hydrox'ylower alkyl radical represents primarily lower alkoxylower alkyl, in which lower alkoxy contains from one to four carbon atoms and represents, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like. The amino group of a tertiary amino-lower alkyl radical is primarily an N,N-di-lower alkyl-amino group, in which lower alkyl contains from one to four carbon atoms, e.g. N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, as well as a l-N,N-lower alkylene-irnino group, in which lower alkylene contains from four to six ring carbon atoms, e.g. l-pyrrolidino, l-piperidino, l-N,N-hexarnethyleneimino and the like, a l-N,N-lower oxa-alkylene-imino-group, in which lower oxa-alkylene contains preferably four ring carbon atoms, e.g. l-morpholino and the like, or a l-N,N-lower azaalkyleneimino group, in which lower aza-alkylene contains from four to six ring carbon atoms, particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino and the like.

The lower alkyl portion in a substituted lower alkyl radical, represented, for example, by R such as in an etherified hydroxy-lower alkyl group and the like, may be a lower alkylene radical containing from two to seven carbon atoms, which separates the substituent, such as the etherified hydroxyl group and the like, from the carbon atom of the carboxy group by at least two carbon atoms. Preferably, such lower alkylene radical contains from two to three carbon atoms and separates the substituent, such as the etherified hydroxyl group and the like, from the carboxy group by the same number of carbon atoms. The alkylene radicals are primarily 1,2-ethylene, l-methyl- 1,2-ethylene, Z-methyl-LZ-ethyleue or Lil-propylene; other lower alkylene radicals may be, for example, 1,4- butylene, l-methyl-Ll-propylene and the like.

The lower alkyl portion of the lower alkoxy group attached to the 17-position of the molecule and represented, for example, by R, in the previously given formula, contains from one to four carbon atoms, and stands for ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, but represents, above all, methyl.

Generally, the etherified hydroxyl group attached to the Ill-position of the yohimbane molecule and represented, for example, by the grouping R in the previously given formula, is etherified by an aliphatic hydrocarbon radical. Such radical representing, for example, the group R stands for lower alkyl, containing from one to seven, preferably from one to four, carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n'pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl and the like.

The ethcrifying group, as represented, for example, by the radical R may also be a substituted aliphatic hydrocarbon radical, such as, for example, an etherified hydroxy-lower alkyl radical, such as lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms and stands, for example, for methoxy, ethoxy, n-propyloxy, n-butyloxy and the like, or a tertiary amino-lower alkyl radical, in which tertiary amino repre sents, for example, N,N-di-lower alkyl-amino, e.g. N,N- dimethylamino, N-ethyl-N-methyl-amino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropylamino, N,N-dibutylamino and the like, N,N-lower alkylene-imino, in which alkylene contains, primarily, from four to six carbon atoms, e.g. l-pyrrolidino, l-piperidino, l-N,N- hexamethyleneimino and the like, l-N,N-lower-oxa-alkylcne-imino, in which alkylene contains, primarily, four carbon atoms, e.g. l-morpholino and the like, l-N,N-lcwer aza-alkylene-imino, in which alkylene contains from four to six ring carbon atoms, particularly 4-lower alkyl-lpiperazino, e.g. 4-methyl-l-piperazino and the like. Preferably, a functional group is separated from the oxygen atom, to which the radical R is attached, by from two to seven, advantageously by from two to three, carbon atoms. Substituted aliphatic hydrocarbon radicals, particularly those representing R are, therefore, 2-lower alkoxy-ethyl, e.g. 2methoxyethyl, Z-cihoxyethyl and the like, 2-lower alkoxy-propyl, e.g. Z-methoxy-propyl, 2- ethoxy-propyl and the like, 3-lower alkoxy-propyl, e.g. 3- methoxy-propyl, 3-ethoxy-propyl and the like, 2-N,N-dilower alkyl-amino-ethyl, e.g. 2-N,N-dirnethylaminoethyl, 2-N,N-diethylaminoethyl and the like, 2-N,N-di-lower alkyl-amino-propyl, e.g. 2-N,N-dimethylaminopropyl, 2- N,N-diethylam.inopropyl and the like, 3-N,N-di-lo'wer alkyl-amino-propyl, e.g. 3-N,N-dimethylaminopropyl, 3-N, N-diethylaminopropyl and the like, 2-N,N-lower alkylene imino-ethyl, e.g. 2( l-pyrrolidino)-ethyl, 2-( l-piperidino)- ethyl and the like, 3-N,N-lower alkylene-imino-propyl, e.g. 3-( l-pyrrolidino)-propyl, 3-(1-piperidino)-propy1 and the like, 2-(4-lower alkyl-l-piperazino)-ethyl, e.g. 2-(4- methyl 1 piperazino) ethyl, 2 (4 ethyl l piperazino)-ethyl and. the like, or 3-(4-lower alkyl-l-piperazino)-propyl, e.g. 3-(4-methyl-l-piperazino)-propyl, 3- (4-ethyl-'lpiperazino)-propyl and the like.

Other etherlfied hydroxyl groups contain as etherifying groups, represented, for example, by the radical R in the above-given formula, other aliphatic radicals, such as, for example, lower alkenyl, such as lower allylic alkenyl, containing preferably from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, Z-butenyl, 3-rnethyl-2- butenyl, Z-pentenyl and the like, cycloalkyl containing from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopcntyl or cyclohexyl, as well as cyclopropyl, cycloheptyl, cyclo-octyl and the like, cycloalkenyl, containing preferably from five to six ring carbon atoms, e.g. 3-cyclopentenyl, 2-cyclohexenyl and the like, cycloalkyl-lower alkyl, in which cycloalkyl contains from three to eight, especially from five to six, ring carbon atoms, and lower alkyl contains from one to four carbon atoms, e.g. cyclopentylmethyl, l-cyclopentyL ethyl, Z-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl and the like, carbocyclic aryl-aliphatic hydrocarbon radicals, such as monocyclic carbocyclic aryllower alkyl, e.g. benzyl, diphenylmethyl, l-phenylethyl, 2-phenylethyl and the like and analogous radicals, in which the carbocyclic aryl nucleus is substituted, for example, by lower alkyl, e.g. methyl, ethyl and the like,

lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, halogeno-lower alkyl, e.g. trifiuoromcthyl and the like, nitro, amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino and the like, or any other suitable substituent, or monocyclic carbocyclic aryl-lower alkenyl, e.g. 3-phenyl-allyl and the like and analogous radicals containing substituents, such as those previously mentioned to be attached to the carbocyclic aryl nucleus.

Additional substituted aliphatic hydrocarbon radicals are particularly lower alkyl radicals substituted by functional groups, such as, for example, by acyl, particularly lower alkanoyl, e.g. acetyl, propionyl and the like, or carbo-lower alkoxy, e.g. carbomethoxy carbethoxy and the like, etherified mercapto, such as lower alkyl-mercapo, e.g. methylmercapto, ethylmercapto and the like, halogeno, e.g. chloro, bromo and the like, or any other substituent suitable for being attached to an aliphatic hydrocarbon, particularly a lower alkyl, radical. These substituted aliphatic radicals are, therefore, primarily lower alkanoyl-lower alkyl, e.g. acetylmethyl, propionylmethyl and the like, carbo-lower alkoxy-lower alkyl, e.g. carbornethoxymethyl, carbethoxymethyl and the like, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, halogeno-lower alkyl, e.g. chloromethyl and the like, as well as other analogous substituents.

Substituents attached to any of the positions available for substitution in ring A, particularly those representing the groups R and R (each of which may also stand for hydrogen) in the previously given formula, may be represented, for example, by lower aliphatic hydrocarbon, especially lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, or by functional groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, containing preferably from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, as well as cycloalkyloxy, e.g. cyclopentyloxy, cyclohexyloxy and the like, cycloalkyllower alkoxy, e.g. cyclopentylmethoxy, 2-cyclopentylethoxy, cyclohexylmethoxy and the like, carbocyclic aryloxy, such as monocyclic car-bocyclic aryloxy, e.g. phenyloxy and the like, carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy, for example, phenyl-lower alkoxy, e.g. benzyloxy, diphenyloxy, IZ-phenylethoxy and the like, esterified hydroxyl, particularly lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, or lower aikanoyloxy, e.g. acetoxy, propionyloxy and the like, etheri'fied mercapto; particularly lower alkyl-mercapto, containing preferably from one to four carbon atoms, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, particularly N,N-disubstituted amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N- ethylN-methyl-amino, N,N'diethylamino and the like, halogeno, e.g. fluoro, chloro, bromo, iodo and the like, halogeno-lower alkyl, e.g. trifluoromethyl and the like, or any other suitable functional group. A substituent may also be attached to two adjacent positions of ring A and form an additional ring; for example, the radicals R and R in the formula, when taken together and substituting two neighboring positions, may also form a cyclic substituent. Such substituents may be represented, for example, by lower alkylene-dioxy, e.g. rnethylenedi oxy, or any other analogous grouping.

Substituents, which may be attached to other positions in the molecule, particularly to the positions available for substitution in ring C are particularly aliphatic hydrocarbon, such as lower alkyl radicals, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl and the like. The radical R in the previously given formula, which stands primarily for hydrogen, may, therefore, also stand for lower alkyl, particularly for methyl.

Salts of the compounds of this inventioniare primarily therapeutically acceptable acid addition salts, particularly those with inorganic acids, particularly with mineral acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, as well as with organic acids, e.g. acetic, tartaric, methane sulfonic acid and the like.

Also included within the scope of the present invention are the N-oxides of the above-mentioned compounds, as well as the therapeutically acceptable acid addition salts of such N-oxides, for example, the addition salts with the above-mentioned inorganic, particularly mineral, and organic acids.

In view of the fact that several asymmetric carbon atoms are present in the compounds of this invention, the latter may be obtained in the form of a mixture of racemates, racemates or optically pure compounds.

The compounds of the present invention have sedative and tranquilizing effects on the central nervous system, as well as antihypertensive properties. In addition, qualitative differences can be observed within the group of the new compounds of this invention. For example, when compared with the ratio existing between antihypertensive and sedative effects in naturally occuring Rauwolfia alkaloids, such as, for example, reserpine, deserpidine, rescinnamine and the like, certain compounds of this invention have more predominant sedative effects with negligible antihypertensive activity, whereas in others, the latter may be more pronounced than the sedative and tranquilizing component.

Furthermore, it has also been found that contrary to the naturally occuring compounds, which show a slow onset of the pharmacological action and an often undesirably long lasting effect, the compounds of this invention react quickly and the activity is of definite duration, i.e. the recovery after treatment is more complete and easily controllable. It has also been found that the therapeutically acceptable salts, particularly those with mineral acids, e.g. hydrochloric acid and the like, are to a high degree water-soluble, and are, therefore, extremely useful in the preparation of aqueous solutions for injection and in aqueous oral preparations, e.g. elixirs and the like.

The compounds of the present invention can, therefore, be used as sedative and tranquilizing agents to relieve states of hyperactivity tension and agitation, as, for example, associated with mental disturbances and the like. Furthermore, they can be used as antihypertensive agents to relieve hypertensive conditions, such as, for example, benign or malignant hypertension, renal hypertension or hypertension associated with pregnancy, such as toxemia of pregnancy. They also can be used as intermediates for the formation of other useful compounds.

, A preferred group of compounds having the abovegiven properties is represented by those of the formula:

in which each of the groups R and R represents lower atoms, especially methyl, as well as ethyl, npropyl, isopropyl, n-butyl, isobutyl, secondary butyl and the like, and R, represents lower alkoxy containing from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is "preferably attached to the l0-position or the ll-position, the therapeutically acceptable acid addition salts, the N-oxides and the therapeutically acceptable acid addition salts of such N-oxides.

An outstanding member of this group of compounds, which has pronounced sedative and tranquilizing effect of fast onset and easily controllable duration, accompanied by negligible antihypertensive properties, is the methyl IS-O-methyl-reserpate of the formula:

and the therapeutically acceptable mineral acid addition salts thereof, such as the hydrochloride and the like.

Other specific compounds of the previously mentioned group are, for example, methyl IS-O-ethyl-rcserpate, methyl l8-0-n-propyl-reserpate, methyl IS-O-isopropylreserpate, methyl IS-O-n-butyl-reserpate, methyl 18 0- isobutyl-reserpate, ethyl IS-O-methyl-reserpate, ethyl l8- O'ethyl-reserpate, ethyl l8-0n-propyl-reserpate, ethyl 18-O-n-butyl-reserpate, n-propyl IS-O-methyl-reserpate, n-propyl l8-0-ethyl-reserpate, isopropyl l8-0-methylreserpate, isopropyl l8-O-n-propyhreserpate, n-butyl l8- O-methyl-reserpate, n-butyl 18-O'ethyl-reserpate, isobutyl IB-O-methyl-reserpate, n-pentyl IS-O-methyl-reserpate, n-hexyl IS-O-methyl-reserpate and the like.

Other compounds of the aforementioned formula are, for example, the lower alkyl l8-0-lower alkyl-9-methoxydeserpidates, e.g. methyl 9-methoxy-lS-O-methyl-deserpidate, methyl 18-O-ethyl-9-methoxy-deserpidate, methyl 9-methoxy-IS-O-n-propyl-deserpidate, ethyl 9-methoxy- IS-O-methyl-deserpidatc and the like, lower alkyl 18-O- lower alkyl-lll-methoxy-deserpidate, e.g. methyl IO-methoxy-lS-O-methyl-deserpidate, methyl 18-O-ethyl-10-meth oxy-deserpidate, methyl IO-methoxy-lS-O-n-propyl-deserpidate, ethyl IO-methoxy-l8-0-methyl-deserpidate, n-propyl lfi-methoxy-l 8-O-methyl-deserpidate, isopropyl 10- methoxy-l-methyl-deserpidate and the like, lower alkyl ll-ethoxy-l8-O-lower alkyl-deserpidate, e.g. methyl llethoxy-l8-0-methyl-deserpidate, methyl ll-ethoxy-l 8-0- ethyl-deserpidate and the like, lower alkyl l8-O-lower al-kyl-l1-n-propyloxy-deserpidate, e.g. methyl 18-O-methyll l-n-propyloxy-deserpidate, methyl l8-O-ethyl-11-n-propyloxy-deserpidate and the like, lower alkyl ll-isopropyloxy-lS-O-lower alkyl-deserpidate, e.g. methyl ll-isopropyloxy-18-O-methyl-deserpidate, ethyl ll-isopropyloxy- IB O-methyI-deserpidate and the like, lower alkyl ll-nbutyloxy-lS-Odower alkyl-deserpidate, e.g. methyl ll-nbutyloxy-lS-O-methyl-deserpidate, methyl l1n-butyloxy- IS-O-ethyI-descrpidate and the like, lower alkyl 18-O-lower alkyl-IZ-methoxy-deserpidates, e.g. methyl IZ-methoxy- ISO-methyl-deserpidate, ethyl 12-methoxy-l8-0-methyldeserpidate and the like.

An additional preferred group of compounds are the lower alkyl 18-0-lower alkyl-deserpidates, in which lower alkyl contains preferably from one to four carbon atoms,

alkyl, containing preferably from one to four carbon 7 and is represented primarily by methyl, as well as ethyl,

n-propyl, isopropyl, u-butyl, isobutyl and the like, the therapeutic-ally acceptable acid addition salts thereof, the N-oxides thereof and the therapeutically acceptable acid addition salts of such N-oxides. Specific members of this group are, for example, methyl IB-O-methyl-deserpidate, methyl IB-O-ethyl-deserpidate, methyl l8-O-n-propyldeserpidate, methyl 18-O-isopropyl-deserpidate, methyl IB-O-n-butyl-deserpidate, methyl l8-O-secondary butyldeserpidate, ethyl IB-O-methyl-deserpidate, ethyl 180- ethyl-deserpidate, ethyl l8-O-n-propyl-deserpidate, n-propyl 18-O-methyl-deserpidate, n-propyl l8-O-ethyl-deserpidate, isopropyl l8-O-methyl-deserpidate, isopropyl 18- O-n-butyl-deserpidate, n-butyl l8-0-methyl-deserpidate, secondary butyl l8-O-methyl-deserpidate, n-pentyl l8-0- methyl-deserpidate and the like.

Other compounds having the useful pharmacological properties previously mentioned, are, for example, lower alkyl 18-O-lower alkyl--methyl-reserpates, e.g. methyl 5- methyl-lS-O-methyl-reserpate, methyl IS-O-ethyl-S-methyl-reserpate, ethyl S-methyl-l8-Omethyl-reserpate and the like, lower alkyl l8-O-lower alkyl-G-methyl-reserpates, e.g. methyl 6-methyl-18-O-rnethyl-reserpate, methyl 18-O- n-butyl-6-methyl-reserpate, ethyl 6-methyl-l8-O-methylreserpate and the like, lower alkyl 18-O-lower alkyl-6- methyl-deserpidate, e.g. methyl G-methyl-lS-O-methyldeserpidate, methyl fi-methyl-18-0-n-propyl-deserpidate, ethyl G-methyl-IS-O-methyl-deserpidate and the like, lower alkyl 18O-lower alkyl-9-methyl-deserpidate, e.g. methyl 9-methyl-l8-O-methyl-deserpidate, methyl 9-methyl-18-O- ethyldeserpidate, n-propyl 9-methyl-1S-O-methyl-deserpidate and the like, lower alkyl 18-O-lo-wer alkyl-l l-methyl-deserpidate, e.g. methyl 1l-methyl-IS-O-methynbdeserpidate, ethyl l1-methyl-1B-O-methyl-deserpidate, ethyl 11- methyl-l8-O-n-butyl-deserpidate and the like, lower alkyl l8-O-lower alkyl-IO-rnethoxy-reserpate, e.g. methyl l0- methoxy-lS-O-methyl-reserpate, methyl l8-0-ethyl-l0- methoXy-reserpate, ethyl lO-methoxy-lS-O-n-propyl-reserpate and the like, lower alkyl l8-O-lower alkyl-10,11- lower alkylenedioxy-deserpidate, e.g. methyl IS-O-methyh 10,11-methylenedioxy-deserpidate, ethyl IB-O-methyl-IO, ll-methylenedioxy-deserpidate and the like, lower alkyl lfl-benzyloxy-lS-O-lower alkyl-deserpidate, e.g. methyl benzyloxy-l8-O-methyl-deserpidate, methyl IO-benzyloxy- IB-O-ethyl-deserpidate, ethyl l0-benzyloxy-l8-O-methyldeserpidate and the like, lower alkyl ll-benzyloxy-l8-O- lower alkyl-deserpidate, e.g. methyl ll-benzyloxy-18-O- methyl-deserpidate, methyl ll-benzyloxy-l B-O-ethyl-deserpidate, ethyl 1l-benzyloxy-18-0-methyl-deserpidate and the like, lower alkyl 18-O-lower alkyl-1 l-methylmercaptodeserpidate, e.g. methyl l8-O-methyl-1l-methylmercaptodeserpidate, methyl IS-O-ethyl-ll-methylmercaptcedeserpidate, ethyl l8-O-methy.l-11-methylmercapto-deserpidate and the like, lower alkyl 1LethyI-mercapto-lS-O-lower alkyl-deserpidate, e.g. methyl ll-ethylmercapto-18-0- methyl-deserpidate, ethyl 18-0-ethyl-1l-ethylmercaptodeserpid-ate, n-propyl ll-ethy1mercapto-IS-O-methybdeserpidate and the like, lower alkyl IO-chloro-lS-O-lower alkyl-deserpidate, e.g. methyl IO-chloro-lS-O-methyldeserpidate, methyl IO-chloro-l8-O-ethyl-deserpidate, ethyl lO-chloro-l8-0-n-butyl-deserpidate and the like, lower alkyl 10-bromo-l8-O-lower alkyl-reserpate, e.g. methyl 10 bromo-IB-O-methyl-reserpate, methyl 10-bromo-18-O-ethyl-reserpate, ethyl lO-bromo-IS-O-ethyI-reserpate and the like, lower alkyl l7a-desmethoxy-l7u-ethoxy-l8-0 lower alkyl-reserpate, e.g. methyl l7m-desmethoxy-l7a-ethoxyl8-0-methyl-reserpate, methyl l7-desmethoxy-l7m-eth-. oxy-l8-0-ethy'l-reserpate and the like, lower alkyl 17a.- desmethoxy-lB-O-lower alkyl-17a-n-propyloxy-reserpate, e.g. methyl 17a-desmethoxy4S-O-methyl-lh-n-propyloxy-reserpate, ethyl l7a-desmethoxy-18-O-methyl-l7a-npropyloxy-reserpate and the like, lower alkyl l7a-desmethoxy 17u-isopropyloxy-l8-0-lower alkyl-reserpate, e.g. methyl 17a: desmethoxy-17a-isopropyloxy-IS-O-methylreserpate, methyl l7e-desmethoxy-l8-0-ethyll7u-isopropyloxy-reserpate and the like, lower alkyl l7a-desmethoxy- 17a-ethoxy-l8-O-lower alkyl-deserpid'ate, e.g. methyl l7adesmethoxy- 17a-ethoxy-1 B-O-methyl-deserpidate, methyl l7a-desmethoxy-17vx-ethoxy-IB-O-ethyI-deserpidate, ethyl 17a desmethoxy-l7a-ethoxy-IS-O-ethyl-deserpidate and the like, or analogous compounds.

Also included in the scope of the invention are, for example, lower alkoxy-lower alkyl 18-O-lower alkylreserpates and lower alkoxy-lower alkyl l8-O-lower alkyldeserpidates, in which lower alkyl of the lower alkoxylower alkyl portion represents a lower alkylene radical which contains from two to three carbon atoms and separates the lower alkoxy group from the carbon atom of the carboxyl group by the same number of carbon atoms, and lower alkoxy has from one to four carbon atoms, whereas the lower alkyl group attached to the oxygen atom of the Iii-position contains from one to four carbon atoms; lower alkoxy-lower alkyl represents, for example, Z-methoxyethyl, 2-ethoxyethyl, 2-methoxypropyl, 3-methoxyethyl and the like, and lower alkyl may stand for methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl and the like. Specific compounds of this group are, for example, Z-methoxyethyl IS-O-methyl-reserpate, Z-methoxyethyl IS-O-ethyl-reserpate, Z-ethoxyethyl 18-O methyl-reserpate, Z-ethoxyethyl IS-O-n-propyl-reserpate, 2-rnethoxypropyl IS-O-methyl-reserpate, 3-methoxypropyl IS-O-methyl-reserpate, Z-methoxyethyl IB-O-methyl-deserpidate, 2-rnethoxyethyl IS-O-ethyl-deserpidate, Z-ethoxyethyl l8-O-methyl-deserpidate and the like.

An additional group of compounds is represented by the N,N-d,i-lower alkyl-amino-lower alkyl l8-O-lower alkyl-reserpates and N,N-di-lower alkyl-amino-lower alkyl l8-O-lower alkyl-deserpidates, in which N,N-di-lower alkyl-amino stands for N,N-dimethylamino, N-ethyl-N- methylamino, N,N-diethylamino and the like, and in which lower alkyl, separating the N,N-di-lower alkylamino group, represents a lower alkylene radical containing from two to three carbon atoms and separating the N,N-di-lower alkyl-amino group from the carbon atom of the carboxyl group by from two to three carbon atoms; N,N-dilower alkyl amino-lower alkyl represents, for example, 2-N,N-dimethylaminoethyl, 2-N,N-diethylaminoethyl, 2-N,N-dimethylaminopropyl, 3-N,N-dirneth ylaminopropyl and the like. Specific compounds of this group are, for example, 2-N,N-dimethylarninoethyl 18-O- methyl-rcserpate, 2-N,N-dimethylaminoethyl l8-O-ethylreserpate, 2vN,N-diethylaminoethyl 18-0- methyl-reserpate, 3-N,Ndimethylaminopropyl l8-O-methyl-reserpate, 2-N,N-dimethylaminoethyl 18 O methyl-deserpidate, 2- N,N-dirnethylaminoethyl l8-O-ethyl-deserpidate, 2-N,N- dimethylaminopropyl IS-O-methyl-deserpidate and the like.

The compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new compounds or derivatives thereof, such as therapeutically acceptable acid addition salts thereof, N-oxides thereof or therapeutically acceptable acid addition salts of N-oxides thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed inert substances which are compatible with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes,-propylene glycol, polyalkylene glyools or any other known inert carrier used in medicaments. The pharmaceutical preparation may be in solid form, for example, as tablets, capsules, dragees and the like, or in liquid form, for example, as solutions, suspension, emulsions and the like. If desired, they may contain additional substances such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers or any other auxiliary substances. They may also contain, in combination, other therapeutically useful substances.

Compounds of this invention can be formed by etherifying in an l8-hydroxy-l7-lower alkoxy-3-epi-allo-yohimbane lo carboxylic acid ester, particularly in a compound of the formula:

in which R R R R, and K, have the previously given meaning, a salt thereof, an N-oxide thereof or a salt of an N-oxide thereof, the free hydroxyl group attached to the IS-position by treatment with a diazo-compound in the presence of a strong inorganic Lewis acid, and, if desired, converting a resulting salt into the free base, and/or, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof, and/ or, if desired, converting a resulting mixture of isomers into the single isomers.

Salts of the starting materials or of an N-oxide thereof, are addition saltswith acids, primarily those with inorganic, such as mineral, acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like. Acid addition salts may also be those with the strong inorganic Lewis acid catalyzing the etherification reaction, e.g. fiuo' boric acid and the like; these salts may be formed during the reaction. a

The starting materials, the salts, the N-ox-ides or the salts of N-oxides thereof are reacted with the aliphatic diam-hydrocarbon, for example, a lower diazo-alkane, particularly diazomethane and the like, as well as with a substituted aliphatic diazo-hydrocarbon, such as an etherified hydroxy-lower diazo-alkane, particularly a lower alkoxy-lower diazoalkane, a tertiary amino-lower diazo-alkane, particularly an N,N-di-lower alkyl-aminolower diazo-alkane and the like, or any other suitable reagent, in the presence of a strong inorganic Lewis acid. Fluoboric acid, which may be employed in the form of a concentrated aqueous solution (for example, an about l2 N to an about 16 N aqueous solution), represents the preferred reagent. Other Lewis acid reagents may be, for example, perchloric acid (preferably in anhydrous form) and the like. Due to the salt-forming properties of the free starting material, the Lewis acid, catalyzing the etherification of the 18-hydroxyl group, is used in excess of one mol, whenever the free base is present; an about one to an about two hundred, preferably an about ten to an about fifty, percent excess appears to be suflicient to promote the etherification reaction.

The reaction is carried out in the presence of solvents, which are inert towards the starting materials and the reaction reagents; such solvents are, for example, halogenated lower aliphatic hydrocarbons, e.g. methylene chloride, chloroform, ethylene chloride, trichloroethane, tetrachloroethane and the like, others, e.g. diethylether, tetrahydrofuran and the like, lower alkyl lower alkanoates, e.g. ethyl acetate and the like, acetonitrile or any other useful solvents, as well as mixtures of such solvents. A solution of the cliazo reagent in an inert solvent such as an ether, e.g. diethylether and the like, or a halogenated hydrocarbon, e.g. methylene chloride and the like, or a mixture of solvents, may be added to the mixture of the starting material and the Lewis acid, preferably kept in solution. The diazo compound may also be distilled out of its solution into the solution of the mixture of the starting material and the Lewis acid. Furthermore, the latter mixture may also be given to a solution of the diazo reagent.

The reaction may be carried out at room temperature; however, cooling of the reaction mixture to below room temperature, for example, to from about 10 to about -20", especially to from about 0 to about l5, may be advantageous. If necessary, the reaction may be carried out in the atmosphere of an inert gas, e.g. nitrogen.

An excess of the diazo reagent present at the end of the reaction may be destroyed, for example, by adding an acid, preferably an easily esterifiable carboxylic acid, e.g. acetic, benzoic acid and the like. The desired product may be isolated and separated from any by-products according to standard procedures, e.g. extraction, adsorption and elution, crystallization, etc. and purified, for example, by recrystallization, if necessary, after treatment of a solution thereof with an adsorbent, e.g. aluminum oxide, charcoal, diatomaceous earth and the like.

The above-described procedure may be illustrated by the treatment of lower alkyl reserpate, particularly of methyl reserpate, with a lower diazo-a1kane, such as diazomethane, in the presence of a strong Lewis acid, such as fluoboric acid and the like, to form the desired lower alkyl l8-O-lower alkyl-reserpate (particularly the desired methyl IS-O-methyl-reserpate, which, if desired, may be converted into an acid addition salt, particularly a mineral acid, e.g. hydrochloric acid and the like, addition salt thereof.

The starting materials are known or, if new, may be prepared according to procedures used for known analogs. Thus, 18-hydroxy-l7-lower alkoxy-3-epi-allo-yohimbane IG-carboxylic acids, such as, for example, compounds of the formula:

in which R R R and R, have the previously given meaning, salts thereof, N-oxides thereof or salts of N- oxides thereof, may be esterified, for example, by treatment with a lower diazo-alkane, or a substituted lower diazo-alkane, such as an etherified hydroxy-lower diazoalkane, a tertiary amino-lower diazo-alkane and the like. For example, to a solution of the diazo reagent in an inert solvent, such as an ether, particularly diethylether, may be added an acid of the above formula, a salt, an N-oxide or a salt of an N-oxide thereof, which is preferably kept in a suspension or a solution, for example, of a lower alkanol, e.g. methanol, ethanol and the like, a halogenated lower aliphatic hydrocarbon, e.g. chloroform, methylene chloride and the like, or any other suitable, inert solvent. Or, the diazo compound may be distilled out of a solution, such as a diethylether solution, into the suspension or solution of the free acid used as the starting material. An excess of the diazo reagent present in the reaction mixture may be destroyed, for example, by adding an additional carboxylic acid, e.g. acetic, benzoic acid and the like. The esterification may be carried out under cooling or at room temperature, and, if desired, under the atmosphere of an inert gas, e.g. nitrogen.

The starting materials may also be prepared by sub- 1 l jecting (16-) l8)-lactones of 18-hydroxy-17-lower alkoxy- 3-epi-alloyohimbane lfi-carboxylic acids, such as, for example, compounds of the formula:

a salt, an N-oxide or a salt of an N-oxide thereof, to alcoholysis with lower alkanols or substituted lower alkanols, such as etherified hydroxy-lower alkanols, tertiary amino-lower alkanols and the like, in the presence of an alcoholysis catalyst. The alcoholyzing reaction may be carried out, for example, by treating the lactone compound used as the starting material with a lower alkanol, or a substituted lower alkanol, such as an etherified hydroxy-lower alkanol, a tertiary amino-lower alkanol and the like, in the presence of an alcoholysis catalyst, for example, an alkali metal, e.g. sodium, potassium and the like, compound of the alcoholysis alcohol, or any other suitable catalyst, eg. potassium cyanide, benzyl trimethyl ammonium hydroxide and the like. Although this reaction may prowed under cooling or at room temperature, the mixture is advantageously heated, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.

N-oxides of the starting material may be prepared according to known N-oxidation methods; for example, a solution of the starting material in an inert solvent may be treated with a per-acid, such as, for example, peracetic, perbenzoic, mono-perphthalic, p-toluene persulfonic acid and the like, with hydrogen peroxide or with ozone and the like.

Salts or salts of N-oxides of the above-mentioned starting material may be prepared by treating the latter or an N-oxide thereof with an acid, particularly an inorganic acid, such as a mineral acid, e.g. hydrochloric, sulfuric, phosphoric acid and the like, preferably in the presence of a suitable solvent.

A modification of the above procedure, which yields IB-etherified hydroxy-17-lower alkoxy-3-epi-allo-yohimbane l-carboxylic acid esters, in which the radical etherifying the IS-hydroxyl group and the group esterifying the lfi-carboxyl group are identical, more particularly the compounds of the formula:

in which R R R R R and R have the previously given meaning, with the proviso that the radical R has the same meaning as the radical R salts, N-oxidesor salts of N-oxides thereof, comprises reacting an 18-hydr0xy-17-lower alkoxy-3-epi-a1lo-yohambane 1 6-carboxylic acid, particularly a compound of the formula:

in which R,,, R R and R have the above-given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, with a lower diazo-alkane or with a substituted lower diazo-alkane, such as an etherified hydroxy-lower diazoalkane, a tertiary amino-lower diazo-alkane and the like, in the presence of a strong Lewis acid and isolating the desired compound, and, if desired, carrying out the optional steps.

This reaction may be carried out according to the previously given method and is catalyzed by the necessary amount of a strong Lewis acid. It may also be carried out in such manner that first the reactive carboxyl group in the lfi-position is esterified. This may be done by adding part (one mol or an excess) of the diazo-reagent to the free acid compound, using appropriate solvents, and, after the addition of the Lewis acid to catalyze the etherification, giving to the reaction mixture the additional amount (one moi or an excess) of the diazo-reagent.

The above reaction may be illustrated by thetreatment of reserpic acid with an excess of diazomethane in the presence of a strong Lewis acid, such as fluoboric acid and the like, and isolation of the desired methyl 1 8-O-methyl-reserpate.

A further method for preparing the compounds of this invention comprises esterifying in iii-etherified hydroxyl7-lower alkoxy-3-epi-allo-yohimbane l6-carboxylic acid compounds, particularly in compounds of the formula:

in which R R R,, R and R have the above-given meaning, salts, N-oxides or salts of N-oxides thereof, the free carboxyl group attached to the l6'position, and, if desired, carrying out the optional steps.

The carboxyl group may be esterified according to known methods; for example, the starting material, preferably a solution thereof, may be treated with a diazoreagent, such as, for example, an aliphatic diazo-hydrocarbon or a substituted aliphatic diam-hydrocarbon. Such reagents are primarily lower diazo-alkanes, e.g. diazomethane, diazoethane, n-diazopropane, diazo-isopropane, n-diazobutane, diazo-isobutene and the like. Other reagents are, for example, etherified hydroxy-lower diazoalkanes, such as lower alkoxy-lower diazo-alkanes, in which lower alkoxy is separated from the diazo group by at least two, preferably by from two to three carbon atoms, e.g. Lmethoxy-diazoethane, Z-ethoxy-diazoethane, 2-n-propyloxy-diazoethane, 3-methoxydiazopropane and the like, tertiary amino-lower diazoalkanes, particularly N,N-di-lower alkyl-amino-lower diazo-alkanes, in which the N,N-di-lower alkyl-amino group is separated from the diazo group by at least two, preferably by from two to three, carbon atoms, e.g. 2-N,N-dimethylamino-diaz0 ethane, 2-N,N-diethylamino-diazoethane, 3-N,N-dimethylamino-diazopropane and the like, as well as other tertiary amino-lower diazo-alkanes. These diazo reagents are advantageously used in solution with an inert diluent, such as, for example, an ether, e.g. diethylether and the like, or they may be distilled out of their solution into a solution of the starting material. An excess of the diam-compound present after the completion of the reaction may be destroyed, for example, by adding an additional carboxylic acid, such as acetic, benzoic acid and the like.

The diazo-reagent may be given to the starting material or a solution thereof; suitable solvents are, for example, ethers, e.g. diethylether, detrahydrofuran and the like, lower alkanols, e.g. methanol, ethanol and the like, halogenated hydrocarbons, e.g. chloroform, methylenechloride and the like, or any other appropriate solvents.

The above procedure may be illustrated by the treatment of IB-O-methyl-reserpic acid with diazomethane to form the desired methyl l8-0-methyl-deserpidate.

The starting materials used in the above procedure, which are intended to be included within the scope of the invention, may be prepared, for example, by converting in an IS-etherified hydroxyl-l7-lower alkoxy-3-epiallo-yohirnlbane l6-carboxylic acid ester, particularly in compounds of the formula:

in which R,, R R R R and R have the above-given meaning, or a salt, an N-oxide or a salt of an N-oxide thereof, the esterified carboxyl group attached to the Iii-position into a free carboxyl group, and, if desired, converting a resulting compound into a salt, an Noxide or a salt of an N-oxide thereof.

Hydrolysis may be carried out according to known methods; for example, the esterified carboxyl group may be cleaved by treatment with an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, in a lower alkanol, e.g. methanol, ethanol and the like, or, preferably, in an aqueous solution of a lower alkanol.

This procedure including the preparation of the starting material may be illustrated, for example, by the hydrolysis of ethyl l8-O-methyl-reserpate furnishing the IS-O-methyI-reserpic acid, which may then be esterificd with a diam-compound other than diazoethane, for example, diazomethane and the like.

As previously mentioned, the starting materials used in the above modification of the procedure for the preparation of the compounds of the invention, are new and are intended to be included within the scope of the invention. Especially useful as intermediates are the compounds of the formula:

in which R represents lower alkyl, particularly methyl and the like, and R, stands for lower alkoxy, particularly methoxy, whereby the latter is preferably attached to the IO-position or the ll-position, salts, N-oxides or salts of N-oxides. This group of compounds may be represented by 18-O-lower alkyl-reserpic acids, e.g. 18-O- methyl-reserpic acid, 1'8-0-ethyl-reserpic acid, 18-0-npropyl-deserpidic acid, l8-0-n-butyl-reserpic acid and the like, 18-O-lower alkyl-IG-methOxy-deserpidic acids, e.g. IO-methoxy-l8-O-methyl-deserpidic acid, IB-O-ethylldmethoxy-deserpidic acid, 10-methoxy-18-O-n-propyldeserpidic acid and, the like, l8-O-lower alkyl -9-methoxydeserpidic acids, e.g. 9-methoxy-l8-Orrnethyl-deserpidic acid and the like, ll-ethoxy-lB-O-lower alkyl-deserpidic acids, e.g. 1l-ethoxy-lS-O methyI-deser idic acid and the like, l8-O-lower alkyl-IQ-methoxy-deserpidic'acids, e.g. IZ-methoxy-l8 O-methyl-deserpidic acid and the like. Another preferred group of compounds are the 18-0- lower alkyl-deserpidic acids, e.g., l8-O-methyl-desenpidic acid, IB-O-ethyl-deserpidic acid and the like, as well as, for example, S-methyl l8-0-methyl-reserpic acid, 6-methyl-lS-O-methyl-deserpidic acid, 9-methyl-l8-O-methyldeserpidic acid, l0-methoxy-l8-O-methyl-reserpic acid, 10-chloro-18-O-methyl-deserpidic acid, l0-bromo-18-O- methyl-reserpic acid, IS-O-methyl-ll-methylmercaptodeserpidic acid, l0,ll-methylenedioxy-lS-O-n-propyl-deserpidic acid, l7-desmethoxy-l7-ethoxy-18-O-methyl-reserpic acid and the like.

The above starting materials may also be prepared, for example, by alcoholysis of a (16 18)-lactone of 18- hydro ry-l'i-lowe'r alkoxy-3-epi-allo-yohimbane l6-carboxylic acid, particularly a lactone of the formula:

in which R,, R R and K, have the previously given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, with an alcohol of the formula rnn-o-c ll 2 in which R R R and R have the previously given meaning, Ph represents monocyclic carbocyclic aryl and Z stands for hydrogen or lower alkyl, a salt, an N-oxide or a salt of an N-oxide thereof, the free hydroxyl group by treatment with a diam-reagent, such as a diazo-com pound of the formula R N in which R, has the previously given meaning, in the presence of a strong inorganic Lewis acid, and converting in a resulting IB-etherified hydroxyl-I7-lower alkoxy-3-epi-allo-yohimbane 16-carboxylic acid ester, particularly in a resulting compound of the formula:

in which R R R R R Ph and Z have the previously given meaning, the esterified carboxyl into a free carboxyl group, and, if desired, converting a resulting free compound into a. salt, an N-oxide or a salt of an N- oxide thereof.

The alcoholysis of the lactone is carried out according to known methods; for example, an alcohol of the formula Ph(Z)CHOI-l, in which Ph and Z have the previously indicated meaning, or a solution thereof in an inert solvent, is reacted with an alkali metal, e.g. sodium, potassium and the like, and the resulting reagent is treated with the lactone or a solution thereof. The reaction may prooeed under cooling or at room temperature, but may be more readily completed by heating, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.

The monocyclic carbocyclic aryl radical Pb in the above alcohol stands primarily for phenyl; it may also represent substituted phenyl, whereby substituents may be lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, or halogeno, e.g. chloro, bromo and the like or any other substituent, which does not hinder the alcoholysis or the subsequent cleavage of the monocyclic carbocyclic arylmethyl radical. Although Z may represent lower alkyl, e.g. methyl, ethyl, n-propyl and the like, it stands primarily for hydrogen.

Etherification of the free hydroxyl group in l8-position may be carried out as previously shown, i.e. by treatment with an appropriate diazo-reagent in the presence of a strong Lewis acid, e.g. fiuoboric acid and the like.

The esterified carboxyl group may be converted to the free carboxyl group, for example, by hydrogenolysis, which may be carried out by treatment of the ester, preferably in solution, for example, in a lower alkanol, e.g. methanol, ethanol and the like, with hydrogen in the presence of a catalyst, which contains a metal of the eighth group of the periodic system, for example, palladium, e.g. palladium black, or any other suitable catalyst. If necessary, an increased pressure, and/or an elevated temperature may be employed, although normally the reaction proceeds under atmospheric pressure and at room temperature. In order to secure a complete hydrogenolysis, the reaction vessel is agitated to expose the catalyst to the hydrogen. The resulting reaction mixture is freed from the catalyst, for example, by filtration, and the desired product may be isolated according to standard methods, for example, by extraction, crystallization, adsorption and elution, and the like and is purified, for example, by recrystallization and the like.

The ester group may also be cleaved by hydrolysis, for example, by the previously described alkaline hydrolysis or by acid hydrolysis, for example, by treatment with a 16 hydrohalic acid, e.g. hydrogen bromide and the like, in a lower alkanoic acid, e.g. glacial acetic acid and the like.

The intermediates used in the preparation of the 18- etherified hydroxyl-l7-lower alkoxy-3-epi-allo-yohimbane lfi-carboxylic acid used as the starting materials, particularly the compounds of the formula:

in which R R R R R Ph and Z have the previously given meaning, are new and are intended to be included within the scope of the invention. Particularly useful intermediates are the compounds of the formula:

in which R represents lower alkyl, particularly methyl and the like, and R stands for lower alkoxy, especially methoxy and the like, whereby the group R is preferably attached to the Ill-position or the ll-position salts, N- oxides or salts of N-oxides thereof. Such compounds are, for example, benzyl l8-O-lower alkyl-reserpates, e.g. benzyl lS-O-methyl-reserpate, benzyl 18-O-ethyl-reserpate and the like, benzyl l8-O-lower alkyl-l0-methoxydeserpidates, e.g. benzyl IO-methoxy-lS-O-methyl-deserpidate, benzyl lO-methoxy-lB-O-n-propyl-deserpidate and the like. Other highly useful intermediates are, for example, the benzyl 18-O-lower alkyl-deserpidates, e.g. benzyl 18-O-methyl-deserpidate, benzyl 18-O-ethyl-deserpidate and the like, or analogous compounds.

Compounds of the present invention may also be ob tained by transesterifying in l8-etherified hydroxy-l7- lower alkoxy-3-epi-allo-yohimbane 16-carboxylic acid ester, particularly in compounds of the formula:

example, by treating the starting material with an alcohol, such as an alcohol of the formula R -OH, in which R; has the above-given meaning, but stands primarily for lower alkyl, particularly lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, propyl, butyl, isobutyl and the like. Alcohols of the formula R -OH are, therefore, primarily lower alkanols such as methanol, ethanol, propanol, butanol or isobutanol and the like. Other alcohols, particularly alcohols of the formula R OH are those, in which R represents substituted lower alkyl, such as etherified hydroxy-lower alkyl, e.g. lower alkoxy-lower alkyl, tertiary amino-lower alkyl and the like, whereby the etherified hydroxy and the tertiary amino groups are separated from the hydroxyl group by from two to seven carbon atoms; such alcohols are, for example, Z-methoxyethanol, 2-ethoxyethanol, 3-methoxypropanol, 2-N,N-dimethyl-ethanol, 2-N,N-diethylaminoethanol and the like.

Transesterification is carried out in the presence of a transesterification catalyst, particularly a basic transesterification catalyst. Such catalysts are, for example, alkoio ide ions, as, for example, furnished by alkali metal lower alkanolates, e.g. lithium, sodium or potassium methanolate, ethanolate, n-propanolate, n butanolate, or isobutanolate and the like, alkaline earth metal lower alkanolates, e.g. barium or strontium methanolate, ethanolate, n-propa-nolate, n-butanolate, or isobutanolate and the like, or aluminum lower alkanolates, e.g. aluminum methanola-te, ethanolate, n-propanolate, isopropanolate, n-butanolate, or isobutanolate and the like. The individual alkanolate compounds are employed together with the corresponding lower alkanol used as the transesterification reagent. Other alcohols such as those of the formula il -OH, in which R represents, for example, substituted lower alkyl, such as etherified hydroxy-lower alkyl, e.g. lower al-koxy-lower alkyl and the like, tertiary aminolower alkyl and the like, may be used in the presence of the corresponding alkali metal, alkaline earth metal or aluminum alcoholates. Other basic tra-nsesterification catalysts are, for example, alkali metal cyanides, e.g. potassium cyanide and the like, or strong quaternary ammonium hydroxides, e.g. benzyl-trimethyl-ammonium hydroxide and the like. The transesterification reaction may also be catalyzed by acidic reagents; inorganic acids, such as tungstic acid and the like, or organic acids, such as ptoluene sulfonic acids and the like, may be used.

Apart from the esterifying alcohols, which may simultaneously serve as diluents, other inert solvents may be used in the above-mentioned transesterification reaction; carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, are examples of such inert solvents. If necessary, the reactionmay be carried out at an elevated temperature, under increased pressure and/or in the atmosphere of an inert gas, e.g. nitrogen.

This method is, therefore, suitable for preparing from compounds of this invention other compounds which are embraced by the generic formula given for the compounds of this invention, and which may not be readily accessible by the other procedures. For example, upon treatment of methyl IS-O-mcthyl-reserpate with a lower alk-anol containing more than one carbon atom, e.g. ethanol, n-propanol and the like, in the presence of a transester-ifying reagent, lower alkyl lS-O-methyl-reserpates may be obtained, in which lower alkyl contains more than one carbon atom. r, alower alkyl'l B-Ornethyl-reserpate, in which lower alkyl contains more than one carbon atom, may be treated with methanol in the presence of a transesterfying reagent, such as, for example, sodium methanolate to form the desired methyl l8-O-methylreserpate.

The compounds of the present invention may also be prepared, for example, by removing in IS-etherified hydroxy-l7-lower alkoxy-B-epi-allo-yohimbane 16-carboxylic acid ester salts, which contain attached to the nitrogen atom representing the d position a substituent, particularly in compounds of the formula:

in which R,, R R R R and R, have the previously given meaning, R represents a group capable of being removed, and A11 stands for an union, the substituent attached to the nitrogen atom of the 4-position, for example, the group R, and, if desired, carrying out the optional steps.

The substituent attached to the nitrogen atom, such as, for example, the radical R in the above formula, may be an altiphatic hydrocarbon radical, such as, for example, lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like, lower alkenyl, such as allylic lower alkenyl, containing preferably from three to five carbon atoms, e.g. ally], Z-methylollyl, Z-butenyl and the like, or any other suitable aliphatic radical. The group attached to the nitrogen atom of the 4-position, as represented, for example, by the radical R, may also stand for a substituted aliphatic hydrocarbon radical; substituting groups may be, for example, carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl, 1- naphthyl, Z-naphthyl and the like, or analogous radicals substituted by additional groups, such as lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, nitro, amino, such as N,N-di-lower alkylamino, e.g. N,N-dimothylamino and the like, or any other suitable group, which does not impede the departure of the whole group attached to the 4-position. Other'substituents attached to the aliphatic hydrocarbon radical may be functional groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, containing preferably from one to tour carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy and the like, carbocyclic aryloxy, particularly monocyclic or bicyclic carbocyclic aryloxy, e.g. phenyloxy and phenyloxy, in which phenyl is substituted by. additional substituents, such as those previously mentioned, earbocyclic aryl-lower aliphatic hydrocarbonoxy, such as monocyclic or bicyclic carbocyclic aryl-lower al-koxy, e.g. benzyloxy, diphenylmethyloxy and the like and analogous groups, in which the carbocyclic aryl nucleus contains additional substituents, such as those mentioned hereinbefore. Other functional groups attached to an aliphatic hydrocarbon radical substituting the nitrogen atom of the 4-position are, for example, etherifiecl mercapto, such as, for example, lower alkylmercapto, e.g. inethylmercapto, ethylmercapto and the like, carbocyclic aryl-mercapto, such as monocyclic or bicyclic oarbocyclicmercapto, e.g. phenylmercapto and the like and phenylmercapto, in which phenyl is sub stituted by the aforementioned substituents, carbocyclic aryl-lower aliphatic hydrocarbon-mercapto, such as monocyclic or bicyclic oarbocyclic aryl-lower alkyl-mercapto, e.g. benzylmercapto, diphenylmethylmercapto and the like, and analogous groups, in which the carbocyclic aryl radical is substituted by the aforementioned substituents, halogeno atoms, e.g. chloro, bromo and the like, carbolower alkoxy, e.g. carbomethoxy, carbethoxy and the like, or any other suitable functional group.

The aliphatic hydt ocmbon group, to which the abovementioned substi-tuents are added, are primarily represented by lower alkylene radicals, above all by the methylene radical, as well as by 1,1-ethylene, LZ-ethylene, 1,1- propylene and the like. Preferred substituted aliphatic hydrocarbon radicals attached to the nitrogen atom of the 4-position, as particularly represented by the group R in the above formula, are, for example, monocyclic carbocyclic aryl-lower alkyl, particularly monocycl-ic carbocyclic aryl-methyl, e.g. benzyl, diphenylrnethyl, trityl and the like, or l-monocyclic carbocyclic aryl-ethyl, e.g. l-phenylethyl and the like, lower alkoxy-lower alkyl, particularly lower alkoxy-methyl, e.g. methcxymethyl, ethonymethyl, n-propyloxymethyl, isopropyloxymethyl and the like, monocyclic carbocyclic aryl-lower alkoxy-lower alkyl, particularly monocyclic carbocyclic aryl lower alkoxy-methyl, e.g. bcnzoyloxymethyl and the like, lower alkyl-mercapto-lower alkyl, particularly lower alkyl-meroaptome-thyl, e.g. methylmercaptomethyl, ethylmercaptomethyl and the like, monocyclic carbccyclic aryl-lower alkyl-mer capto-lower alkyl, especially monocyclic carbocyclic andlower alkyl-mercaptomcthyl, e.g. benzylmercapbomethyl and the like, halogeno-lower alkyl, primarily halogenomethyl, e.g. chloromethyl, bromomethyl and the like, carbo-lowelr alkoxy-lower alkyl, particularly carbodower alkoxy-methyl, eg carbomethoxyrnet hyl, carbethoxymethy] and the like.

The anion of the salts used as the starting materials, especially the anion represented by the group A11 in the above formula, stands primarily for the anion of a strong inorganic, especially mineral, acid, e.g. hydrochloric, hydnobromic, hydriodic, sulfuric, fiuoboric acid and the like, or of a strong organic, particularly a strong organic sulfonic, acid, e.g. p-tolnene sul-fonic acid and the like.

The group attached to the nitrogen atom of the 4 position, as represented, for example, by the group R in the above formula, may be removed according to methods, the selection of which depends primarily on the nature of this group.

The substituent may be cleaved off by pyrolysis at an elevated temperature, preferably under reduced pressure, and, if desired, in a high-boiling solvent and/or in the atmosphere of an inert gas, e.g. nitrogen.

Specifically substituted groups may be removed by other procedures. For example, monocyclic carbocyclic arylmethyl or l-monocyclic carbocyclic arylcthyl groups, such as benzyl, diphenylmethyl, trityl, l-phenylethyl and the like, as well as monocyclic carbocyclic aryl-lower alkoxymethyl, e.g. benzoyl-oxymethyl, diphenylmothoxymethyl and the like, or any other analogous substitnenlt, may be removed by hydrogenolysis, for example, by treatment with hydrogen in the presence of a catalyst containing a metal of the eighthgroup of the periodic system, e.g. nickel, palladium and the like. Other groups, such as, for example, etherified hydroxy'mcthyl, such as lower alkoxymethyl, e.g. methoxymethyl and the like, or any other ethe-rified hydroxymethyl group, e.g. benzyloxymethyl and the like, h-alogenomethyl, e.g. chloromethyl and the like, carbo-lower alkoxy-methyl, e.g. car-bornethoxyrnethyl, carbeflio xymemyl and the like, my be re moved by hydrolysis, for example, by treatment with a dilute inorganic acid, such as, for example, hydrochloric, sulfuric acid and the like. Still other groups, represenh ing, for example, the substituent R in the above formula, particularly etherified mercaptomethyl, such as lower alkyl-mercaptomethyl, e.g. methylmercaptcmcthyl, ethylmercaptomethyl and the like, earbocyclic aryl-memapto methyl, particularly monocyclic aryl-mercaptlomethyl, e.g. phenylmercaptomethyl and the like, or carbocyclic a-ryllower aliphatic lrydrocarbommercaptomethyl, such as mono-cyclic carbocyclic aryl-lower alkyl mercaptomethyl, e.g. benzylmercaptomethyl and the like, may be removed by desulfurization in the presence of a hydrogenation catalyst, particularly a catalyst a metal of the eighth group of the periodic system, e.g. Raney nickel, palladium black and the like.

The starting materials used in the above procedure may 20 be obtained according to dilferent methods. For example, an 18-hydroxy-17-lower alkoxy-3-epi-allo-yohimb=ane l6-carboxylic acid ester, particularly a compound of the formula:

in which R R R R and R have the previously given meaning, or a salt thereof, may be treated with a reactive ester of an aliphatic hydroxy-hydrocar-bon compound or a reactive ester of a substituted aliphatic hydroxy'hydiocarbon compound, which contains as a substituent one of the above-mentioned groups, represented, for example, by the compound of the formula R-OH, in which R has the previously given meaning, and, if necessary, the 18-hydroxyl group in a resulting 18-hydroxy-17-lower alkoxy-3-epi-alloyohimbane IG-carboxylic acid ester salt, which contains an aliphatic hydrocarbon or a substituted aliphatic hydrocarbon attached to the nitrogen atom of the 4-posi-tion, particularly in a resulting compound of the formula:

in which R R R R R R and An have the previ ously given meaning, may be etherificd and the desired star-ting materials may be isolated.

Reactive esters of aliphatic hydroxy-hydrocarbon and substituted aliphatic hydroxy-hydrocarbon compounds are particularly those with strong inorganic acids, particularly strong mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or with strong organic acids, such as organic sulfonic acids, e.g. p-toluene sulfonic acid and the like. The reaction is carried out in the absence or presence of an inert solvent, under cooling, at room temperature or at an elevated temperature, and, if necessary, under pressure or in the atmosphere of an inert gas, e.g. nitrogen.

The etherification of the free hydroxyl group in the 18- position may occur simultantously with the introduction of a removable group into the 4-position. Or, a free 18- hydroxyl group in a resulting compound may then be etherified as previously shown, for example, by treatment with an aliphatic diam-hydrocarbon, particularly a lower diazo-alkane, such as diazomethane and the like, or a substituted aliphatic diam-hydrocarbon, such as an etherified hydroxy-lower diazo-alkane and the like, if necessary, in the presence of a strong Lewis acid, such as fluoboric acid and the like.

Introduction of the desired group into the 4-position of an l8-hydroxy-l7-lower alkoxy-3-epi-allo-yohimbane 16- carboxylic acid ester or a salt thereof may occur by treatment with a diazo-reagent, such as an aliphatic diazohydrocarbon, particularly a lower diazoalkane, especially diazomethane and the like, or a substituted aliphatic diazohydrocarbon. The reaction is carried out in the presence ill in which R,, R R R R R R and A11 have the previously given meaning. This group may be illustrated by the compounds of the formula:

in which each of the radicals R and R stands for lower alkyl, particularly methyl and the like R represents lower alkoxy, especially methoxy and the like, whereby R is preferably attached to the IO-position or the ll-position, R stands for lower alkyl, especially methyl and the like, monocyclic carbocyclic aryl-lower alkyl, particularly monocyclic carbocyclic aryl-methyl, e.g. benzyl and the like, or l-monocyclic oarbocyclic aryl-methyl, e.g. l-phenylethyl and the like, etherified hydroxy-lower alkyl, such as lower alkoxy-lower alkyl, particularly lower alkoxymethy l, e.g. methoxymethyl and the like, monocyclic carbocyclic aryl-lower alkoxy'lower alkyl, particularly monocyclic carbocyclic aryilower alkoxy-methyl, e.g. benzyloxymethyl, diphenyloxymethyl and the like, lower alkyl-mercapto-lower alkyl, particularly lower alkyl-mercaptomethyl, e.g. methylmercaptomethyl and the like, halogeno-lower alkyl, particularly halogenomethyl, e.g. chloromethyl and the like, or carbo-lower alkoxy-lower alkyl, such as carbo-lower alkoxy-methyl, e.g. carbomethoxy-methyl and the like, and A11 represents the anion of a strong acid, primarily a strong inorganic acid. Another preferred group of starting materials may be represented by the compounds of the formula:

in which R R;,', R and A11 have the above-given meanthe Specific starting materials, useful in the above-described procedure, particularly the compounds of the formula:

in which R R R R R R R and A11 have the previously given meaning, with the proviso that the groups R R and R have the same meaning, may also be obtained, for example, by treating a (16 18)-lactone of an l8-hydroxy-l7-lower alkoxy-3-epi-allo-yohimbane 16-carboxylic acid, particularly a compound of the formula:

in which R R R and R have the previously given meaning, or a salt thereof, with a tri-substituted oxonium fluoborate and recovering the desired compound.

The above-mentioned tri-substituted oxonium fluoborate reagent may be represented, for example, by tri-lower alkyl-oxonium fluoborate, especially by trimethyl-oxonium fluoborate, as well as triethyl oxonium fluoborate and the like. The reaction with this reagent is preferably carried ,out in the presence of an inert solvent, if necessary, at an elevated temperature, and, if necessary, under presure or in the atmosphere of an inert gas, e.g. nitrogen,

The above reaction, i.e. treatment of a (16+ 18)-lactone of 18-hydroxy-17-lower alkoxy-3-epi-allo-yohimhane 16- carboxylic acid with a tIi-substituted oxonium fluoborate, may also yield the desired IS-etherified hydroxyl7- lower alkoxy-3-api-allo-yohimbane lfi-earboxylic acid esters directly as a by-product, particularly the 17,18-di-lower alkoxy-S-epi-allo-yohimbane l6-carboxylic acid lower alkyl esters, such as those of the formula:

R IE

in which R R R and R, have the previously given meaning, and the radicals R and R representing lower alkyl, have the same meaning, whenever the lactone, used as the starting material, is reacted with a tri-lower alkyl-oxonium fluoborate. The formation of the compounds of this invention according to the above procedure is, therefore, also included within the scope of the invention; it may be illustrated by the reaction of the (l6- l8)-lactone of reserpic acid with trimethyl oxonium fluoborate, preferably in the presence of a diluent, and isolation of the desired methyl 18-0-methyl-reserpate.

An additional procedure useful for the preparation of compounds of the present invention comprises removing in IS-etherified hydroxyl-l7-lower alkoxy-B-epi-allo-yohimbane l6-carboxylic acid N-oxides, particularly in compounds of the formula:

in which R,, R R R R and R or salts thereof, the oxygen atom ataehed to the nitrogen atom in the 4-position, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into a salt thereof.

The oxygen atom may be removed by treatment with a reducing reagent, for example, with hydrogen in the presence of a catalyst, which contains a metal of the eighth group of the periodic system, such as nickel, platinum, palladium and the like, e.g. Raney nickel, platinum oxide and the like, or with nascent hydrogen, as generated, for example, by heavy metals, e.g. iron, zinc, tin and the like, in the presence of acids, e.g. acetic acid and the like, or with any other appropriate reducing reagent or method.

The starting materials used in the above reaction may be prepared, for example, by etherifying in an l8-hydroxy-l7- lower alkoxy-3-epi-allo-yohimbane l6-carboxylic acid ester N-oxide, particularly in a compound of the formula:

in which R R R R and R have the previously given meaning, or a salt thereof, the 18-hydroxyl group. This etherification may be carried out by treatment with an aliphatic diazo-hydrocarbon, such as lower diazo-alkane, particularly diazomethane and the like, or a substituted ali phatic diam-hydrocarbon, preferably in the presence of a strong Lewis acid, e.g. fluoboric acid and the like, in the presence of a suitable solvent according to the previously outlined method, or by treatment with any other etherification reagent suitable for the etherification of a secondary hydroxyl group.

The N-oxides used as intermediates for the preparation of the starting materials are known, or, if new, may be prepared according to methods used for the preparation of known compounds.

The compounds of the present invention may also be prepared by removing in IS-etherified hydroxy-l7-lower alkoxy-allo-yohimbane l6-carboxlic acid esters, in which a double bond extends from the 3-position or salts of such compounds, par-ticularly in compounds of the formula:

lip

in which R R R R R and R have the previously given meaning, and in which a double bond extends from the 3-position, or salts thereof, the double bond extending from the 3-position by reduction and, if desired, carrying out the optional steps.

In the above starting materials the double bond extends probably from the 3-position to the l4-position, or, in the salts thereof, from the 3-position to the 4-position.

The anion in the above-mentioned salts stands primarily for the anion of a strong inorganic acid, particularly a mineral acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, or phosphoric acid, a halogenophosphoric acid, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable acid. It may also represent the anion of an organic acid; a salt with an organic acid may be present whenever a solution of the starting material in an organic acid, e.g. acetic acid and the like, is used in the above-described removal procedure.

The removal of the double bond may be carried out with the help of a reduction procedure, particularly by treating a solution of the starting material in an acid, such as, for example, acetic acid (preferably in the form of aqueous acetic acid), perchloric acid and the like, with a metal. Together with the acid the metal furnishes the reducing reagent capable of reducing the double bond; zinc, in the presence of an acid, e.g. acetic, percbloric acid and the like, yields a very useful reducing reagent. Zinc in the presence of perchloric acid, which may be used in an aqueous mixture or in admixture with another acid, e.g. acetic acid, represents the preferred reagent; this reagent is particularly suitable because the rate of reduction is fast and any contact of the starting material, as well as the reduction product with the acidic medium can be kept to a minimum. Organic diluents, such as ethers, e.g. tetrahydrofuran, p-dioxan and the like, lower alkanones, e.g. acetone and the like, or any other suitable solvent may be present as additional diluents, if desired, together with water. The reduction may he carried out at room temperature, or, if necessary, under cooling or at an elevated temperature.

The product of the reduction procedure may be isolated, for example, by neutralizing the reaction mixture with an alkaline reagent, e.g. ammonia and the like, if desired, after removing the solvent or part of it, and extracting the organic material with a solvent, e.g. methylene chloride and the like, or by any other suitable isolation method.

The above procedure may be illustrated, for example, by the treatment of methyl n -clehydro-ltl-O methyl-reserpate, in which the double bond probably extends from the 3-position to the l4-position, or a methyl A -dehydro- IS-O -methyI-reserpate salt, in which the double bond extends from the 3-position to the 4-position, with zinc in the presence of an acid, e.g. acetic, perchloric acid and the like, and the isolation of the desired methyl 18-0- methyl-reserpate.

The starting material, which is used in the above procedure and has the previously given formula, is new and is intended to be included within the scope of the present invention. A preferred group of starting materials has the previously given formula and is particularly represented by the compounds of the formula:

in which each ofthe groups R and R stands for lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like, and R stands for lower alkoxy, containing preferably from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, n-butyloxy and the like, whereby R is preferably attached to the l-position or the ll-position, and in which a double bond extends from the 3-position to the 14-position, and salts of such compounds, in which a double bond extends from the 3-position to the 4- position, especially salts containing as the anion portion an anion derived from an inorganic, particularly a mineral, acid, such as one of those mentioned hereinabove. Specific examples of this group of starting materials are, for example, lower alkyl A -dehydro-l8-O-lower alkyl-re serpa'tes, e.g. methyl d -dchydro-lS-O-rnethyl-reserpate, methyl A -dehydro-1B-O'ethyl-reserpate, methyl A dehydro-l80-n-propy-l-reserpate, methyl M-dehydro-liS-O-m butyl-reser-pate, ethyl A -dehydro-I8-O-methyl-reserpate, ethyl .M-dehydro-d8-O-ethyl-reserpate, n-propyl A -dehydro-lB-O-methyl-rescrpate, isopropyl M-dehydro-lE-O- methyhreserpatc, n-butyl M-dehydro-lS-O-methyl-rcserpate and the like, lower al=kyl M-dehydro-lS-Odower alkyl-l0-methoxy-deserpidates, e.g. methyl A -dehydro-l0- methoxy-18-O-methyl-deserpidate, methyl A -dehydr0-18 O-ethyl-I O-methoxy-deserpidate, methyl A -dehydro-l8-0- n-butyl methoxy-deserpidate, ethyl A -dehydro-10 methoxy-IS-O-methyl-desenpidate, ethyl A -dehydro-10- methoxy-lB-O-n-propyl-deserpidate, n-propyl A -dehydro- 10-methoxy-18-0-methyl-deserpidate, isopropyl M-dehydro-lO-methoxy-18-O-methyl-deserpidate and the like, in which the double bond probably extends from the 3-position to the l t-position, and salts of such compounds, in which the double bond extends from the 3-position to the 4-position, as well as lower a-lkyl A -dehydro-l8-0-lo'wer alkyl-9rnethoxy-reserpate, e.g. methyl A -dehydro-9-meth- Oxy-lB-O methyl-deserpidate, methyl M-dehydro-lS-O-ethyl-9-methoxy-deserpidate, ethyl Adehydro-Q-methoxy-IS- O-methyl-deserpidate and the like, lower alkyl A -dehydroll-ethoxy-l S-O-lower alkyl-deserpidate, e.g. methyl A -dehydro-l1-ethoxy-IS-O-methyI-deserpidate, methyl M-dehydro-1 l-ethoxy- 1 8-0ethyl-deserpidate, n-propyl A -dehydro-l l-ethoxy-l S-O-methyl-deserpidate and the like, lower alkyl A ,-dehydro-18-0-lower alkyl-lZ-methoxy-deserpidate, e.'g. methyl A -dehydro-l2-methoxy-l8-O-rnethyl-desenpidate, ethyl A -dehydro-12-methoxy-l8-O-n-propyl-deserpid-ate and the like, in which the double bond probably extends from the 3-position to the 14 position, and salts of these compounds, in which the double bond extends from the 3-position to the 4-position.

Another group of very usefiul intermediates are, for example, lower alkyl n -dehydro-l 8-0-lower alkyl-deserpidates, e.g. methyl M-dehydro-lS-O-methyl-deserpidate, methyl M-dehydro-l8-0-ethyl-deserpidate, methyl A -dehydro-18-O-n-butyl-deserpidate, ethyl A -del1ydro-18-O- methyl-desenpidate, ethyl M-dehydro-lS-O-n-propyl deserpidate, n-propyl A -dehydrod8-0-methyl-deserpidate, isopropyl n -dehydro-l S-O-methyl-deserpidate, n-butyl A -de- 26 hydro-18-0-methyl-deserpidate and the like, in which the double bond probably extends from the 3-position to the 14-position, and the salts of these compounds, in which the double bond extends from the 3-position to the 4-position. Salts of the above-mentioned compounds contain as anions those of inorganic, particularly mineral, acids, such as hydrohalic acids, e.-g. hydrochloric, hydrobromic acid and the like, phosphoric acid, halogenophosphoric acids, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable inorganic acid, as well as organic acids, e.g. acetic acid and the like.

The above-mentioned starting materials may be prepared, for example, by etherifying in an l8-hydroxy-l7- lower alkoxy-3-oxo-2,Zl-seco-allo-yohimbane 16-carbox. ylicl acid ester, particularly in a compound of the formu a:

in which R,, R R R and R have the previously given meaning, the free hydroxyl group in the 18-position, and converting the resulting l8-etherified hydroxy-17-lower alkoxy-3-oxo-2,3-seco-allo-yohimbane 16-carboxylic acid ester, particularly the resulting compound of the formula:

in which R R R R R and R, have the previously given meaning, into the desired starting material by ring closure, and, if desired, converting a resulting salt into the free base.

The etherification of the free hydroxyl group of the 18- position in the 2,3-seco-compound can be carried out according to known etherification procedures. For example, treatment with an aliphatic diam-hydrocarbon, such as a lower diazo-alkane, particularly diazornethane and the like or a substituted aliphatic diam-hydrocarbon, for example, as in the previously described procedure in the presence of a Lewis acid, such as, for example, fluoboric acid and the like, alfords the desired etherification. The latter may also be carried out by treatment with other reagents suitable for the etherification of a secondary hydroxyl group. Such reagents are, for example, reactive esters formed by aliphatic hydroxy-hydrocarbon compounds, such as lower alkanols, particularly methanol, as well as ethanol and the like, or by substituted aliphatic hydroxy-hydrocarbon compounds with strong acids, such as inorganic acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or with organic acids, particularly strong organic sulfonic acids, eg, p-toluene sulfonic acid and the like, which reagents are preferably used in the presence of reagents facilitating the etherification procedure. Especially useful are di-lower slkyl sulfates, particularly dimethyl sulfate, as

27 well as diethyl sulfate and the like, which reagents are preferably used in the presence of a base, such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, lower alkyl halides, especially methyl chloride, methyl bromide, methyl iodide and the like, as well as ethyl, n-propyl or n-butyl chloride, bromide or iodide and the like, which reagents are preferably used in the presence of a basic reagent, such as, for example, silver oxide and the like, or any other suitable etherification procedure.

Ring closure of the resulting ether compound can be achieved, for example, by treatment with an acidic ring closing reagent, for example, phosphoric acids, e.g. polyphosphoric acid and the like, phosphorus halides, e.g. phosphorus trichloride, phosphorus pentachloride, or advantageously phosphorus oxyhalides, e.g. phosphorus oxychloride and the like.

The conversion of a resulting salt, in which the double bond extends from the 3position to the 4-position, particu larly of a salt having the partial formula:

in which R has the previously given meaning, and An represents an anion, derived, for example, from the acidic ring closing reagent, into the free base, in which the double bond extends probably from the 3-position to the l t-position, particularly into a compound having probably the partial formula:

in which R has the previously given meaning, can be carried out according to known methods, for example, by treatment of the salt with a base, particularly ammonia, as well as an alkali metal carbonate, e.g. sodium, potassium carbonate or hydrogen carbonate and the like. Under acidic conditions, as, for example, prevailing in the reduction procedure, the free base forms a salt, in which the double bond extends from the 3-position to the 4-position.

The IS-etherified hydroxy-l7-lower alkoxy-3-oxo-2,3- seco-allo-yohimbane l6-carboxylic acid esters, which are used as intermediates for the preparation of the starting materials, particularly the compounds of the following formula:

in which R R R R R and R have the previously 28 given meaning, are new and are intended to be included within the scope of the present invention. Particularly useful as intermediates are the compounds of the formula:

in which each of the radicals R and R represents lower alkyl, preferably containing from one to four carbon atoms, especially methyl, as well as ethyl, n-proply, isopropyl, n-butyl, secondary butyl and the like, and R represents lower alkoxy, especially lower alkoxy containing from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby such lower alkoxy group R is preferably attached to the 10-position or the ll-position. Specific compounds of this group are, for example, lower alkyl l8-O-lower alkyl-3-oxo-2,B-seco-reserpates, e.g. methyl l8-O-methyl-3oxo-2,3-seco-reserpate, methyl 18- O-ethyl-3-oxo-2,3-seco-reserpate, methyl l8-O-n-propyl-3- oxo-2,3-seoo-reserpate, methyl l8-O-n-butyl-3-oxo-2,3- seco-reserpate, methyl 18-O-isobutyl-3-oxo-2,3-seco-reserpate, ethyl l8-O-methyl-3-oxo-2,3-seco-reserpate, ethyl l8-O-n-propyl-3-oxo-2,3-seco-reserpate, n-propyl l8 0- methyl-3-oxo-2,3-seco-reserpate, n-propyl 18-O-ethyl-3- oxo-2,3-seco-reserpate, isopropyl l8-O-methyl-3-oxo-2,3- seco-reserpate, isopropyl 18-O-n-butyl-3-oxo-2,3-secoreset-pate, n-butyl 18-0-methyl-3-oxo-2,3-seoo-reserpate and the like, or lower alkyl 18-Olower alkyl-IO-methoxy- 3-oxo-2,3-seco-deserpidates, e.g. methyl IO-methoxy-lS-O- methyl-3-oxo2,3-seco-deserpidate, methyl 18-O-ethyl 10 methoxy-3-oxo-2,3-seco-deserpidate, methyl IO-methoxy- 18-0-n-propyl-3-oxo2,3-seco-deserpidate, methyl 18-O-nbutyl-l0-methoxy-3-oxo-2,3-seco-deserpidate, ethyl 10- methoxy-l8-0-metl1yl-3-oxo-2,3-seoo-deserpidate, ethyl 18-O-ethyl-l0-methoxy-3-oxo2,3-seco-deserpidate, n-propyl lO-rnethoxy-18-0-methyl-3-oxo-2,3-seco-deserpidate, n-propyl 1S-O-ethyl-l0-methoxy-3-oxo-2,3-seco-deserpidate, isopropyl lO-methoxy-18-O-methyl-3-oxo-2,3-secodeserpidate and the like, as well as lower alkyl 18-O-lower alkyl-9-methoxy-3-oxo-2,3-seco-deserpidates, e.g. methyl 9 methoxy l8 O methyl-3-oxo-2,3-seco-deserpidate, methyl 18-0-ethyl-9-methoxy-3-oxo-2,3-seco-deserpidate, ethyl 9-methoxy-18-O-rnethyl-3-oxo-2,3-seco-deserpidate and the like, lower alkyl ll-ethoxy-lS-O-lower alkyl-3- oxo-2,3-seco-deserpidates, e.g. methyl ll-ethoxy-lS-O- methyl-3-oxo-2,3-seco-deserpidate, methyl l1-ethoxy-18- 0-n-propyl-3-oxo-2,3-seco-deserpidate and the like, lower alkyl l8-O-lower alkyl-12-methoxy-3-oxo-2,3-seco-deserpidates, e.g. methyl l2-methoxy-l8-0-metl1yl-3-oxo- 2,3-seco-deserpidate, ethyl 12-methoxy-18-O-methyl-3- oxo-2,3-seco-deserpidate and the like. Another group of highly useful intermediates are the lower alkyl l8-0-lower alkyl-3-oxo-2,3-seco-deserpidates, e.g. methyl 18-0- methyl-3-oxo-2,3-seco-deserpidate, methyl l8-O-ethyl-3- oxo-2,3-seco-deserpidate, methyl 18-O-n-propyl-3-oxm 2,3-seco-deserpidate, methyl l8-0-n-butyl-3-oxo-2,3-secodeserpidate, ethyl 18-O-methyl-3-oxo-2,3-seco-deserpidate, ethyl 18-O-ethyl-3-oxo 2,3-seco-deserpidate, n-propyl l8-0-methyl-3-oxo-2,3-seco-deserpidate, n-propyl 18-0-11- propyl-3-oxo-2,3-seco-deserpidate, isop-ropyl IS-O-methyl- 3-oxo-2,3-seco-deserpidate, n-butyl l8-0-methyl-3-oxo- 2,3-seco-deserpidate and the like.

The intermediates used for the preparation of the starting materials of the described procedure may also be obtained, for example, by etherifying in an ester of 3p-hy- 29 droxy-2a-lower alkoxy-7-oxo-la,2p,3a,4,7,8,9a,loot-octahydronaphthalene-lfl-carboxylic acid of the formula:

in which R;,, as well as R have the previously given meaning, whereby R represents particularly lower alkyl, particularly methyl, as well as ethyl, n-propyl, isopropyl, n-butyl and the like, the hydroxyl group in the Sfl-position according to known methods used for the etherification of a secondary hydroxyl group, for example, by treatment with a diazo compound, such as a lower diazo-alkane, particularly diazomethane and the like, in the presence of an etherification catalyst, particularly 'fluoboric acid and the like, as previously described. The resulting a,fiketone is then oxidized, for example, with osmium tetroxide, in an aqueous solution, followed by treatment with sodium chlorate, to form an ester of smfia-dihydroxy-Sfl-etherified hydroxy-Za-lower alkoxy-7-oxo-la,2fl, 3u,4,5fi,6fl,7,8,9,10u decahydronaphthalene 1p earboxylic acid having the formula:

in which R R and R have the above-given meaning, which diol is then oxidatively split, for example, by treatment with periodic acid hydrate in an aqueous medium, to a monoester of the Sfl-aldehydo'Bp-etherified hydroxy- 6p carboxyrnethyl 2n: lower alkxy-la,2fl,3m,4,5ot,6ahexahydrobenzene-lfl-carboxylic acid of the formula:

in which R R, and R halve the previously given meaning, and R," represents, for example, hUWGl alkyl, particularly methyl, as well as ethyl and the like. This com- 30 pound is then reacted with a trylptamine, particularly a tryptamine compound of the formula:

in which R R and R, 'have the above-given meaning, preferably in solution with an inent solvent, e.g. benzene and the like, to yield a A -lll-ethe nified hyldnoxy-3,l7- di-lower allcoxy-3-oxo-2,3 3,4- bis seco-ullo-yohim=b-ane l6- oarhoxyl io acid ester, particularly a compound of the formula:

in which R R R R R R and R, have the previouslygivonmisfiormedflnwhichflmeesterified carboxyl groups may be partially or totally hydrolized. Hydmlized earboxyl groups may subsequently be re-esterified (for example, with a lower aliphatic du'azohydrocarbou, such as a lower diazoallnane, particularly diazomethamaswellasdiazoethaneandthelikeormyoflier suitable dnt). Treatment of the eatenwith a dehydrating agent, such as, for example, a OBIbOXYliC acid anhydride, eg. acetic acid arr-hydride and the like, causes ning closure to the desired IS-etherified hydroxy-U-lower allooxy-B-oxo-Zfieeooallmyohimrbane 16-ea|rlboxy1i|c acid ester, which is used as the starting material in the above reaction and which may be illustrated by the oompounds of the formula:

31 in which R R R R R and R have the previously given meaning.

In the above described procedure for the manufaemre of intremedia-tes a number of new compounds, having useful properties as intermediates, are being mourned, which are intended to be included within the scope of the present invention.

Import-ant intermediates, are, for example, compounds of the formula:

in which R R, and R, have the above-given meaning. Particularly useful intermediates are the lower alkyl Zamethoxy-7-oxo-3fllower al-koxy-la,25,3m,4,7,8,9a,IOu-octahydronaphthnlene-lflmrboxylates, in which lower alkyl, containing from one to {our carbon atoms, represents primarily methyl, as well as ethyl, n-pnopyl and the like, and lower alkoxsy, containing from one to four carbon atorns, stands primarily for methoxy, as well as ethoxy, nn-propylox-y and the like, particularly methyl 2,3;8-dimeuhoxyJ-oxo-la,2fl,3a,4,7,8,9a,l0a ootahydronaphthalene-lfl-carboxylate and the like.

Other important and new intermediates are oompounds of the tommmla:

in which R R and R have the previously given meaning. These intermediates are illustrated by the lower alkyl 50:,6a-djhYdl0XY-2a-In6th0XY-17-0XO-3B-[OW6I' alkoxy 1a,2fi,3a,4,5fl,6fi,7,8,9a,10a deoahydronaphthalenelfi-carboxylate's, in which lower alkyl, containing from one to four carbon atoms, represents primarily methyl, as well asethyl, n-propyl and the like, and lower alkoxy, containing from one to four carbon atoms, stands particularly for methoxy, as well as ethoxry, n-propylbxy and the like, especially by methyl $a,6a-dihYdlOXY-2u,3fldi lower alkoxy 7 oxo 1a,2,8,3m,4,5fl,6fl,7,8,9a,l00tdecahydronaphthalene lfl-carboxylate and the like.

A further series of important intermediates are the compounds of the formula:

in which R R and K, have the perv'iously given meaning. This group of intermediates may be represented by lower alkyl Sfi-aldehydoB-carboxymethyl-h-methoxy- 3fl-lower alkoxy-la,2fl,3a,4,5a,6u-helrahydrobenzene-lflcarbomylates, in which lower alkyl, containing from one to four carbon atoms, represents primarily methyl, as well as ethyl, n'propyl and the like, and lower alkoxy, containing from one to four carbon atoms, stands particularly for methoxy, as well as ethoxy, n-propyloxy and 32 the like, [primarily by methyl Sp-aldehydotSp-carboxymethyl 201,3,9 d imet'hoxy 1a,2fl,3nt,4,5at,6a. hexahydrobenzene-lfl-carboxylate land the like.

An additional group of important intermediates is represented by compounds of the formula:

in which R R R and R have the previously given meaning. This group of intermediates is represented by lower alkyl 5fi-aldehydo-6fl-carbo-lower alkoxy-methyl- 2a-methoxy-3fl-lower alkoxy-1a,2B,3a,4,5a,6a,-hexahydrobenzene-lficarboxylate, in which lower alkyl, contairnnlg from one to four carbon atoms, represents primarily methyl, as well as ethyl, n-propyl and the like, and lower alkoxy, containing from one to four carbon atoms, stands particularly for methoxy, as well as ethoxy, n-propyloxy and the like, and especially by methyl 5paldehydo 6p carbomethoxy methyl 2a,3p dimethoxy la,2fl,3a,4,5nt,6a hexahydrobenzene lfl carboxylate and the like.

Additional intermediates useful in the preparation of the starting material and thus in the process of the invention are the A -etherified-hydroxy-3,17-di-lower alkoxy 3 0x0 2,3;3,4-bis-seco-allo-yohimbane l6 carboxylio acid esters, particularly the compounds of the formula:

in which R1, R1,, R2, R3, R4, R5 and R6 have the PI'CViously given meaning, or salts thereof. Each of the rad- :icals R R and R; represents primarily lower alkyl, containing from one to four carbon atoms, especially methyl, as well as ethyl, n-propyl and the like. This group of intenmediates may be represented by compounds of the formula:

alkoxy group is preferably attached to the S-position or the 6-position of the indole portion of the molecule, or salts thereof. This group of intermediates may be represented by the lower alkyl A )-dehydro-3-lower alkoxy- IS-O-lower alkyl-3-oxo-2,3;3,4-bis-seoo-resenpates, particularly by the methyl M -dehydro-il-methyblS-O-methy-l-3-oxo-2,3;3,4-bis-seco-reserpate, as well as analogous compounds, and acid addition salts thereof.

Another group of important intermediates is represented by the compounds of the formula:

in which each of the radicals R R and R represents lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl and the like, or salts thereof. I

A further group of important intermediates are the 18- etherified hydmxy-3,17-bis-lower alkoxy-3-oxo-2,3;3,4- bis-seco-al'lmyohimbane lG-carboxylic acid esters, particularly the compounds of the formula:

in which R R1", R R R R and R have the previously given meaning, or salts thereof. Each of the radicals R R and R represents primarily lower alkyl, containing from one to four carbon atoms, particularly methyl, as well as ethyl and the like. These compounds may be represented by the compounds of the formula:

in which the radicals R and R have the same meaning and stand for lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as Well as ethyl and the like, R represents lower alkyl, containing preferably from one to four carbon atoms,

particularly methyl, as well as ethyl and the like, and

R represents lower alkoxy, containing preferably from one to four carbon atoms, especially methoxy as well as ethoxy and the like, or salts thereof. This group of intermediates is represented by the lower alkyl 3-lower a1k0xy-l8-O-l0wer alkyl-3-oxo-2,3;3,4-bis-secoreserpates, particularly by methyl 3-methoxy-l8-O-methyl-3-oxo-2,3; 3,4-bis-seco-reserpate, or salts thereof.

Another group of important intermediates is represented by the compounds of the formula:

in which each of the radicals R R and R represents lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl and the like, or salts thereof.

A further method for the preparation of the compounds of this invention comprises isomerizing IS-etherified hydroxy-l'Z-lower alkoxy-allo-yohimbane lfi-carboxylic acid esters, particularly compounds of the formula:

in which R R R R R and R have the abovegiven meaning, salts, N-oxides or salts of N-oxides thereof, by treatment with an acid and isolating the desired IS-etherified hydroxy-17-lower -alkoxy-3-epi-allo-yohimbane ItS-carboxylic acid esters, particularly the desired compounds of the formula:

in which R R R R R and R have the above given meaning, salts, N-oxides or salts of N-oxides thereof, and, if desired, carrying out the optional steps.

Acids used in the above isomerization procedure are, for example, organic carboxylic acids, particularly aliphatic hydrocarbon carboxylic acids, such as lower alkanoic acids, eg acetic, propionic acid and the like, primarily glacial acetic acid, organic sulfonic acids, particularly carbocyclic aryl sulfonic acids, e.g. p-toluene sulfonic acid and the like, or lower alkane sulfonic acids, e.g. methane sulfonic acid and the like, or strong mineral acids such as hydrohalic acids, e.g. hydrogen chloride and the like, or mixtures of acids. For example, carbocyclic aryl sulfonic acids are advantageously used together with one of the aliphatic hydrocarbon carboxylic acids mentioned above, for example, p-toluene sulfonic acid in glacial acetic acid. The reaction may be carried out in the absence or presence of an additional solvent; for example, p-toluene sulfonic acid may also be used in the presence of an organic base, e.g. collidine and the like, whereas hydrogen chloride may be used in an anhydrous lower alkanol, e.g. methanol, ethanol and the like. Isomerization may occur at room temperature or preferably at an elevated temperature, in an open vessel or under pressure, preferably in an atmosphere of nitrogen.

Optimum yields in the isomerization reaction may be obtained by removing the desired product from the reaction milieu, thus displacing the reaction equilibrium in favor of the product. The removal may be accomplished by separating the product, if desired, in the form of a salt thereof, from the starting material by exploiting the different relative solubilities in diiferent solvent systems. For example, the product or a salt thereof may be separated from the starting material or a salt thereof either by adsorption on a suitable material, such as alumina, paper and the like, and subsequent fractional elution, or by fractional crystallization from a solvent or a mixture of solvents. The starting material separated from the desired product may then be recycled into the isomerization process, to enhance the overall yield of the reaction.

The starting materials used in the above procedure are new and are intended to be included within the scope of the invention. The 18-etherified hydroxy-l7-lower alkoxy-allo-yohirnbane IG-carboxylic acid esters, such as those of the above-given formula, are particularly illustrated by the compounds of the formula:

in which each of the radicals R and R represents lowor alkyl, containing preferably from one to four carbon atoms, especially methyl, as well as ethyl, n-propyl, isopropyl and the like, and the radical R stands for lower alkoxy, containing preferably from one to four carbon atoms, especially for methoxy, as well as ethoxy, n-propyloxy and the like, whereby R is preferably attached to the l-position or the ll-position, acid addition salts, N-oxides or acid addition salts of N-oxides thereof. This group of compounds is represented by lower alkyl 18-O- lower alkyl-S-iso-reserpates, e.g. methyl 18-0-methyl-3- iso-reserpate, methyl l8-O-ethyl-3-iso-reserpate, methyl 18-0-n-propyl-3-iso-reserpate, ethyl l8-O-methyl-3-isoreserpate, ethyl l8-O-ethyl-3-iso-reserpate, n-propyl 18- O-methyl-3-iso-reserpate, and the like, as well as by lower alkyl 18-0-lower alkyl-ltl-methoxy-ii-iso-deserpidates, e.g. methyl IO-methoxy-l8-O-methyl-3-iso-dcserpidate, methyl 1S-O-ethyl-IO-methoxy-S-iso-deserpidate, ethyl 10-methoxy-l8-0-methyl-3-iso-deserpidate and the like, or the acid addition salts thereof. Other compounds of the above-given type are the lower alkyl 18-0-lower alkyl-9- methoxy-J-iso-deserpidates, e.g. methyl 9-methoxy-l8-O- methyl-3-iso-deserpidate, methyl l8-O-ethyl-9-methoxydeserpidate, ethyl 9-methoxy-18-O-methyl-3-iso-deserpidate and the like, lower alkyl ll-ethoxy-l8-O-lower alkyl-3-iso-deserpidates, e.g. methyl ll-ethoxy-lB-O-methyl-3-iso-deserpidate, ethyl ll-ethoxy-lS-O-n-propyl-B-isodeserpidate and the like, lower alkyl 18-0-lower alkyl- 1Z-methoxy-3-isodeserpidate, e.g. methyl 12-methoxy- 18-O-methyl-3 iso deserpidate, methyl 18-0-ethyl-l2- 36 methoxy-3-iso-deserpida'te and the like, or acid addition salts of such and analogous compounds.

Another group of important starting materials useful in the above isomerization procedure are the lower alkyl 18-O-lower alkyl-B-iso-deserpidates, e.g. methyl 18-0- methyl-B-isodeserpidate, methyl l8-O-ethyl-3-iso-deserpidate, methyl l8-O-n-propyl-3-iso-deserpidate, ethyl 18-0- methyl-3-iso-deserpidate, ethyl l8-O-ethyl-3iso-deserpi date and the like, or salts of such compounds.

The l8-etherified hydroxy-l7-lower alkoxy-allo-yohimbane l6-carboxylic acid esters used as the starting materials in the isomerization procedure may be prepared, for example, by removing in IB-etherified hydroxy-l7- lower alkoxy-allo-yohimbane l6-carboxylic acid esters, in which a double bond extends from the 3-position to the l4-position, or salts thereof, in which a double bond extends from the 3-position to the 4-position, particularly in compounds of the formula:

in which R R R R R and R have the previously given meaning, in which a double bond extends from the 3-position to the l4-position, or salts thereof, in which a double bond extends from the 3-position to the 4-p0sition, the double bond extending from the 3-positi0tl t either the 4-position or the l4-position, and, if desired,- converting a resulting salt into the free compound, and, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof.

The above-mentioned removal may be carried out by catalytic hydrogenation, for example, by treatment with hydrogen in the presence of a catalyst containing a metal of the eighth group of the Periodic System, e.g. nickel and the like, such as Raney nickel and the like, preferably in the presence of a solvent, such as a lower alkanol, e.g. methanol, ethanol and the like, or any other suitable diluent. The reduction may be carried out at normal or under an increased pressure, and/or under cooling, at room temperature or at an elevated temperature. The removal of the double bond may also be accomplished by treatment with a light metal hydride, particularly a borohydride, such as an alkali metal borohydride, etg. lithium borohydride, sodium borohydride, potassium borohydridc and the like, an alkaline earth metal borohydride, e.g. calcium borohydride, barium borohydride, strontium borohydride and the like, or an alkali metal lower a1- koxy-borohydn'de, e.g. sodium trimethoxy-borohydride and the like. These reagents are preferably used in the presence of a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, or a formamide, e.g. formamide, N,N-dimethylformamide and the like or any other suitable diluent. The temperature may, if necessary, be elevated, and the reaction may be can ried out under the atmosphere of an inert gas, e.g. nitrogen. The reduction of the double bond extending from the 3-position may also be carried out by treatment with a. metal amalgam in the presence of a moist solvent, such as an alkali metal amalgam, e.g. sodium amalgam and, the like, or aluminum amalgam in the presence of moist ether or any other suitable moist solvent.

The starting materials used in the isomerization procedure may also be produced, for example, by etherifyin'g: in 18-hydroxy-l7-l0wer alkoxy-allo-yohimbane l.6-car-- ammo boxylic acid esters, particularly in compounds of the formula:

in which R,, R R R R and R have the above-given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, the free hydroxyl group attached to the Ill-position, and, if desired, carrying out the optional steps.

The above etherification of the secondary hydroxyl group attached to the l8-position may be carried out as previously shown, for example, by treatment with a diazo-reagent, such as an aliphatic diam-hydrocarbon, such as a lower diazo-alkane, particularly diazomethane, as Well as diazoethane, diazo-n-propane and the like, or a substituted aliphatic diam-hydrocarbon, such as, for example, an etherified hydroxy-lower diazo-alkane and the like, in the presence of a strong Lewis acid, such as fluoboric acid and the like.

The compounds of this invention may also be prepared, for example, by replacing in an Ill-reactive esterified hydroxy-17-lower alkoxy-3-epi-allo-yohimbane 16car boxylic acid ester, particularly in a compound of the formula:

in which R,, R R R and R have the previously given meaning, and E represents a reactive esterified hydroxyl group, a salt, an N-oxide or a salt of an N-oxide thereof, the reactive esterified hydroxyl group attached to the 18- position by an etherified hydroxyl group, and, if desired, carrying out the optional steps.

The hydroxyl group attached to the 18-position, which is reactively esterified, and is represented, for example, by the group B in the above formula, is preferably esterified by an organic sulfonic acid, such as an aliphatic hydrocarbon sulfonic acid, particularly lower alkane sulfonic acid, especially methane sulfonic acid and the like, or a monocyclic carbocyclic aryl sulfonic acid, especially p-nitro-benzene sulfonic acid and the like. The reactively esten'fied hydroxyl group, particularly the group B in the above formula, may, therefore, be represented by methane sulfonyloxy, p-nitro-benzene sulfonyloxy or analogous reactive esterified hydroxyl groups.

Replacement of the esterified hydroxyl group by an etherified hydroxyl group may be carried out by solvolysis, for example, by treatment with an alcohol of the formula R -0H, in which R, has the previously given meaning. Solvolysis reagents are, therefore, aliphatic hydroxy-hydrocarbon compounds, such as lower alkanols, particularly methanol, as well as ethanol, n-propanol, isopropanol, nbutanol and the like, or substituted aliphatic hydroxyhydrocarbon, such as etherified hydroxy-lower alkanols and the like. The reaction may be carried out in the presence of a diluent, such as an excess amount of the solvolysis reagent, particularly a lower alkanol, such as methanol and the like, or another solvent, for example,

N,N-dimethylformamide, acetonitrile or an analogous solvent, such as a tertiary base and the like. Preferably, solvolysis occurs at an elevated temperature, for example, under reflux, if necessary, under increased pressure or in the atmosphere of an inert gas, e.g. nitrogen.

The replacement of the above-described reactive esterified hydroxyl group by an etherified hydroxyl group, may also occur by treatment with a metal compound of an alcohol of the formula R3-0H, in which R; has the previously given meaning. Particularly useful as reagents are the alkali metal, e.g. lithium, sodium, potassium and the like, compounds of aliphatic hydroxy-hydrocarbons, such as lower alkanols, especially methanol, as well as ethanol, n-propanol and the like, or of substituted aliphatic hydroxy-hydrocarbons. The treatment of the starting materials with these metal reagents is preferably carried out in the presence of a solvent, such as, for example, N,N-dimethyl-formamide, aoetonitrile and the like, if desired, in the presence of the alcohol forming the metal compound, such as a lower alkanol, particularly methanol, as well as ethanol and the like, and, if necessary, at an elevated temperature, under increased pressure and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.

The starting materials used in the above procedure may be prepared according to methods used for the manufacture of analogous compounds. For example, the free hydroxyl group in an l8-hydroxy-l7-lower alkoxy-Il-epiallo-yohimbane l6-carboxylic acid ester may be esterified by treatment of the mono-ester with a reactive derivative of an acid, particularly a halide, e.g. chloride and the like, thereof, in the presence of a tertiary base, e.g. pyridine and the like.

An additional procedure for the preparation of the compounds of this invention, particularly of 'l S-methoxy- 17-lower alkoxy-3-epi-allo-yohimbane IG-esterified carboxylic acid esters, such as those of the formula:

in which R,, R R R and R have the previously given meaning, and the grouping R "O represents an etherified hydroxyl group capable of being converted into another etherified hydroxyl group, particularly into a methoxy group, or a salt thereof, the etherified hydroxyl group into another etherified hydroxyl, particularly into a methoxy, group, and, if desired, carrying out the optional steps.

In the above starting materials, the etherified hydroxyl group attached to the ls-position is primarily represented by a methoxy group, which contains as a substituent a functional group capable of being replaced by a hydrogen atom. Such functional groups are, for example, etherified mercapto, such as lower alkylmercapto, e.g. methylmercapto, ethylmercapto and the like, carboxyl, halogeno, e.g. chloro, bromo and the like, or any other group, which can be replaced by hydrogen.

The above substituents are replaced by hydrogen according to methods, the selection of which depends primarily on the nature of the different functional groups representing these substituents. For example, etherified mercapto groups may be removed by treatment with a hydrogenation catalyst, containing preferably a metal of the eighth group of the periodic system, e.g. nickel and the like, such as Raney nickel or analogous hydrogenation catalysts. Or, a halogen atom may be replaced by hydrogen, for example, by treating the starting material with catalytically activated hydrogen, for example, hydrogen in the presence of a palladium-containing catalyst, or any other suitable hydrogenation procedure. A carboxyl group may be removed by decarboxylation, preferably at an elevated temperature. Other substituents may be replaced by hydrogen while using appropriate methods.

The starting materials used in the above procedure may be prepared, for example, by removing in IS-etherified hydroxyl-l7-lower alkoxy-3-epi-allo-yohimbane l6-carboxylic acid ester salts, in which the etherified hydroxyl group is capable of being converted into another etherified hydroxyl group, and in which the nitrogen atom representing the 4-position carries a substituent capable of being removed, the substituent attached to the nitro gen atom of the 4-position. The removal of the latter may be carried out according to previously shown meth- Ods. The removal of the substituent attached to the 4- position to form the starting materials may occur simultaneously with the conversion of the etherified hydroxyl group of the Iii-position into another etherified hydroxyl group, and the desired formation of the desired final products.

The above-described intermediates used for the preparation of the starting materials may be obtained, for example, by etherifying in an l8-hydroxy-l7-lower alkoxy- 3-epi-allo-yohimbane lfi-carboxylic acid ester salt, which carries a removable substituent attached to the 4-position, the free hydroxyl group in the IS-position into an etherified hydroxyl group, which in the process of the invention is then capable of undergoing the transformation into the desired etherified hydroxyl group. This etherification may be performed according to previously described methods.

The compounds of the present invention, as well as the starting materials and intermediates used in their formation, may be present in the form of mixtures of racemates, single racemates or antipodes. Racemates of intermediates and final products may be resolved into antipodes. Racematcs of final products or intermediates, which form acid addition salts, may be resolved, for example, by treating a solution of the free racemic base in a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, a halogenated lower aliphatic hydrocarbon, e.g. methylenechloride, chloroform and the like, or any other suitable solvent, with one of the optically active forms of an acid containing an asymmetric carbon atoms, which may be employed in solution, for example, in one of the above-mentioned solvents. A salt may then be isolated, which is formed by the optically active acid with one of the optically active forms of the base. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D- and L- tartaric acid, as well as the optically active forms of di-o- '40 toluyl-tartaric, malic, rnandelic, camphor-lO-sulfonic. quinic acid and the like.

Compounds, containing functional groups forming salts with bases, may be resolved by reacting the free acid with the optically active form of a base containing an asymmetric carbon atom and thus forming a salt of such base with one of the optically active forms of the acid compound. Suitable, optically active bases are, for example, the optically active forms of brucine, strychnine, quinine, cinchonine, cinchonidine and the like.

Compounds, which contain neither acid, nor basic saltforming functional groups, but have hydroxyl groups as substitucnts, may be converted into half-esters with dicarboxylic acids, for example, tetrahydrophthalic acid and the like; the resulting acidic compounds may then be resolved as shown hereinabove and the resulting, optically active half-ester may be hydrolyzed to the desired optically active compounds.

The optically active forms may also be obtained by resolution with biochemical methods.

From a resulting salt, the free and optically active compounds may be obtained according to known methods used for the conversion of a salt into a free compound, for example, as outlined hereinbelow; a resulting optically active base may be converted into an acid addition salt with one of the acids mentioned hereinbefore.

The compounds of this invention or the N-oxides thereof may be obtained in the form of the free bases or as the salts thereof. A salt including the salt of an N-oxide, may be converted into the free base, for example, by reacting the former with an alkaline reagent, such as, for example, aqueous ammonia and the like. A free base or the free N-oxide thereof may be converted into its therapeutically useful acid addition salts with one of the inorganic or organic acids outlined hereinbefore; the reaction may be carried out, for example, by treating a solution of the free base in a suitable solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, a halogenated aliphatic hydrocarbon, c.g. methylene chloride, chloroform and the like, with the acid or a solution thereof and isolating the resulting salt. The salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.

N-oxides of the compounds of the present invention may be formed according to known methods; for example, a resulting compound, preferably a solution thereof in an inert solvent, may be reacted with an N-oxidizing reagent, such as, for example, hydrogen peroxide, ozone, persulfuric acid, or more especially, organic peracids, such as organic percarboxylic acids, e.g. peracetic, perbenzoic, monoperphthalic acid and the like, or persulfonic acids, e.g. p-toluene persulfonic acid and the like. Inert solvents are, for example, halogenated lower alkanes, e.g. methylene chloride, chloroform, ethylene chloride and the like, lower alkanols, e.g. methanol, ethanol and the like, or any other suitable solvent. In the N-oxidation reaction an excess of the oxidation reagent and/or an in crease in temperature should be avoided in order to prevent oxidative degradation.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out. It also includes any new intermediates, which may be formed in one of the procedures outlined hereinbefore.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The present application is a continuation-in-part application of our application Serial No. 837,357, filed September 1, 1959, now abandoned, which in turn is a continua- 

10. A COMPOUND OF THE FORMULA: 